Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=1.[OH-].[Na+].C(O)(=O)C>O>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][N:27]=1
Reactant: O=C1CCC(c2ccccc2O)=NN1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2ccccc2O)n[nH]1
Yield: 82.9 %

Procedure:
Sodium 3-nitrobenzenesulphonate (2.96 g) and 6-(2-hydroxyphenyl)-4,5-dihydro-3(2H)pyridazinone (2.5 g) were added to a stirred solution of sodium hydroxide (1.31 g) in water (25 ml) and the mixture was heated under reflux for 2.5 hours. Acetic acid was added to the warm stirred solution until there was no further precipitation and the mixture was pH 9. The mixture was filtered to give 6-(2-hydroxyphenyl)-3(2H)-pyridazinone (2.05 g) m.p. 287°-292°. A sample recrystallised from 2-methoxyethanol had m.p. 295°-299°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH:18]1([C:22]2([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:24][O:23]2)[CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][C:22]([CH:18]3[CH2:21][CH2:20][CH2:19]3)([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:23])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Fc1ccc(C2(C3CCC3)CO2)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccc(F)cc2)C2CCC2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.5 g, 6 mmol) was dissolved in DMF (15 mL) and stirred for 5 min. Sodium hydride (720 mg, 10 mmol) was then added portionwise under nitrogen. This was followed by addition of 2-cyclobutyl-2-(4-fluorophenyl)oxirane (1.906 g, 18 mmol) at RT, and the reaction mixture was stirred for 18 h. After completion of reaction, the reaction mixture was poured into ice water and the product extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by silica gel (#100-200 mesh) column chromatography using 1% MeOH in DCM as eluent. The pure compound was converted into the oxalate salt. 1H NMR (CDCl3, oxalate salt) δ (ppm): 7.30 (d, 1H), 7.20 (m, 2H), 6.95 (m, 4H), 4.20 (m, 1H), 4.0 (m, 1H), 3.80 (m, 2H), 3.10 (m, 1H), 2.70 (m, 4H), 2.50 (s, 3H), 2.20 (m, 2H), 2.0 (d, 1H), 1.80 (t, 2H), 1.70 (m, 1H).
Reaction SMILES: [C:1](CC(O)=O)#[N:2].C(O[C:11](=[O:13])[CH3:12])(=O)C.[CH2:14]([NH:18][C:19]([NH:21][CH3:22])=[S:20])[CH:15]([CH3:17])[CH3:16].[OH-].[Na+]>C(O)C>[NH2:2][C:1]1[N:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:19](=[S:20])[N:21]([CH3:22])[C:11](=[O:13])[CH:12]=1
Reactant: N#CCC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=S)NCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cn1c(N)cc(=O)n(C)c1=S
Temperature: 60 °C
Yield: 28.9 %

Procedure:
A solution of cyanoacetic acid (1.52 g, 17.8 mmol) in acetic anhydride (2.45 mL, 25.9 mmol) was added to 1-isobutyl-3-methylthiourea (2.37 g, 16.2 mmol). The reaction mixture was heated to 60° C. for 1.5 h. The solvent was evaporated and the resulting red oil was redissolved in ethanol (5 mL) and 5M sodium hydroxide (1.6 mL, 8.1 mmol) was added. The reaction mixture was refluxed for 2 h. The solvent was co-evaporated with ethanol and the resulting pale brown solid was purified by flash chromatography (ethyl acetate) to yield 6-amino-1-isobutyl-3-methyl-2-thioxo-1H-pyrimidin-4-one (1.0 g, 29%) as a yellow solid.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[S:22](Cl)(=[O:24])=[O:23].C(OCC)(=O)C.Cl>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[S:22]([NH2:1])(=[O:24])=[O:23]
Reactant: N
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(S(N)(=O)=O)c2)c1=O

Procedure:
With stirring, 1.6 g (93.8 mmol) of ammonia gas were, at 0° C., introduced into a mixture of 18 g (44.6 mmol) of 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-(2H)-pyrimidin-1-yl]-benzenesulfonylchloride in tetrahydrofuran (THF). Then, at 10° C., ethyl acetate was added and the mixture was acidified with 1N hydrochloric acid. The phases were separated and the aqueous phase was extracted, and the combined organic phases were then washed, dried and the solvent was removed. Customary purification methods gave 14.4 g (82.4% of theory) of the title compound (m.p.: 257-258° C.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[O:9]1[CH2:13][CH2:12][CH2:11][C:10]1=O>O>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([N:1]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:9])[CH2:3][CH2:4]1
Reactant: O=C1CCCO1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: O
Product: O=C1CCCN1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
Heat a mixture of trans-4-amino-cyclohexanol (7.36 g, 63.89 mmol) and dihydro-furan-2-one (5 g, 58.08 mmol), in neat, up to 190° C. for 68 h. Cool the mixture to room temp. Dissolve the residue in water and extract with CH2Cl2 (5×100 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 184 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>CC(C)=O>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCn1c(=O)c2c(ncn2S(C)(=O)=O)n(CCCC)c1=O
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To 500 mg (1.89 mmol) of 1,3-dibutyl-3,7-dihydro-purine-2,6-dione in 30 mL of acetone at 23° C. was added 1.04 g (7.56 mmol) of potassium carbonate followed by 0.15 mL (216 mg, 1.89 mmol) of methanesulfonyl chloride. After stirring at 23° C. for 30 min, the reaction mixture was filtered, the filtrate collected and evaporated to give a white solid. This solid was then triturated with 30 mL of petroleum ether to give 500 mg (1.46 mmol, a 77% yield) of the title compound as a white crystalline solid. mp: 98-100° C.; 1H NMR (300 MHz, CDCl3); δ 0.93-0.99 (m, 6H), 1.42-1.49 (m, 4H), 1.55-1.58 (m, 2H), 1.60-1.70 (m, 2H), 3.85 (s, 3H), 3.99-4.04 (m, 2H), ), 4.05-4.16 (t, 2H), 8.17 (s, 1H), 8.55; IR (KBr, cm−1): 3144w, 2965m, 2938m, 2876w, 1715s, 1663s, 1537s, 1442m, 1397s, 1182s, 1131,m, 761m, 670m; MS (ES) m/z (relative intensity): 343 (M++H, 100).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.CO.Cl>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.4 g, 4.2 mmol) (538 mg, 1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (1.1 g, 78%) which was obtained as a white solid. MS: m/e=327.3 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:16]([O-:18])=[O:17])=[CH:13][NH:14][N:15]=2)=[CH:6][CH:5]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.[C:34](#N)[CH3:35]>>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[N:15]([C:30]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:32])([F:33])[F:21])=[CH:28][CH:27]=3)=[O:31])[NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:34][CH3:35])=[O:17])[O:11]2)=[CH:8][CH:9]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC#N
Reactant: O=C([O-])C1=CNN=C(c2ccc(OC(F)(F)F)cc2)O1
Product: CCOC(=O)C1CNN(C(=O)Nc2ccc(C(F)(F)F)cc2)C(c2ccc(OC(F)(F)F)cc2)O1

Procedure:
1 g of the ethyl 5,6-dihydro-2-(4-trifluoromethoxy-phenyl-4H-1,3,4-oxadiazine-6-carboxylate prepared above in A was dissolved in 15 ml of acetonitrile. 1 g of 4-(trifluoromethyl)phenyl isocyanate was added dropwise. The resulting reaction mixture was refluxed for two hours and then the solvent was evaporated under reduced pressure to produce a solid. The solid was washed with a few milliliters of acetonitrile to produce 1.2 g of ethyl 5,6-dihydro-2-(4-trifluoromethoxyphenyl)-N-(((4-trifluoromethylphenyl)amino)carbonyl)-4H-1,3,4-oxadiazine-6-carboxylate as a white solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:16][C:13]1([CH3:17])[N:12]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
A solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (33.6 mg, 0.140 mmol) prepared in Process 3 of Example 12 in dichloromethane (2 mL) was added sequentially with benzoyl chloride (40.0 mg, 0.280 mmol), triethylamine (56.6 mg, 0.560 mmol), and DMAP (catalyst amount) at room temperature, and the resultant was stirred at the same temperature for 1.5 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=3:1), and the title compound (40.4 mg, 85.3%) was obtained as a white crystalline powder.
Reaction SMILES: CC([O-])(C)C.[K+].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[CH:15][S:16][C:9]=12.COC(=O)CC[S:22][C:23]1[CH:24]=[C:25]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:26]([NH:29][C:30]2[S:31][CH:32]=[C:33]([CH2:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[N:34]=2)=[N:27][CH:28]=1>CS(C)=O>[O:49]([C:25]1[C:26]([NH:29][C:30]2[S:31][CH:32]=[C:33]([CH2:35][CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[N:34]=2)=[N:27][CH:28]=[C:23]([S:22][C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[CH:14]=[CH:15][S:16][C:9]=23)[CH:24]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: Clc1ccnc2ccsc12
Reactant: COC(=O)CCSc1cnc(Nc2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)cs2)c(Oc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Added potassium 2-methylpropan-2-olate (0.443 g, 3.95 mmol) to a solution of 7-chlorothieno[3,2-b]pyridine (0.268 g, 1.58 mmol) and tert-butyl 4-((2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate (0.77 g, 1.32 mmol) in DMSO (8 mL). The reaction was stirred for two hours, then set aside to react at ambient temperature for 60 hours. The reaction was partitioned between ethyl acetate and saturated ammonium chloride. Washed the organic layer twice with water and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 1:1 hexane:ethyl acetate. The major UV active component with an Rf of 0.3 was collected and concentrated to afford the title compound (0.810 g, 97.4% yield) as a white powder: 1H NMR (CDCl3) δ 8.88 (s, 1H), 8.46 (d, 1H), 8.32 (s, 1H), 7.72 (d, 1H), 7.54 (d, 1H), 7.38 (t, 2H), 7.20 (t, 1H), 7.18 (s, 1H), 7.04 (d, 2H), 6.73 (d, 1H), 6.51 (s, 1H), 4.09 (m, 2H), 2.68 (m, 2H), 2.59 (d, 2H), 1.87 (m, 1H), 1.66 (m, 2H), 1.45 (s, 9H), 1.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1)=[O:7])[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-ethoxy--benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Ethoxy-N-(4-nitro-3-trifluromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: C(OC(=O)[N:7]([C@H:9]([C:11](=[O:43])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]#[N:38])[N:23]=2)[C:17]2[CH:39]=[CH:40][CH:41]=[CH:42][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])(C)(C)C.[C:45](Cl)(=[O:55])[C:46]1[CH:54]=[CH:53][C:49]([C:50]([Cl:52])=[O:51])=[CH:48][CH:47]=1>>[ClH:52].[ClH:52].[C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH2:21][N:18]2[C:17]3[CH:39]=[CH:40][CH:41]=[CH:42][C:16]=3[N:15]([C:45](=[O:55])[C:46]3[CH:54]=[CH:53][C:49]([C:50]([N:15]4[C:16]5[CH:42]=[CH:41][CH:40]=[CH:39][C:17]=5[N:18]([CH2:21][C:22]5[C:30]6[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=6)[N:24]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=6[C:37]#[N:38])[N:23]=5)[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:43])[C@@H:9]([NH:7][CH3:8])[CH3:10])[CH2:14]4)=[O:51])=[CH:48][CH:47]=3)[CH2:14][C@H:13]([NH:12][C:11](=[O:43])[C@@H:9]([NH:7][CH3:8])[CH3:10])[C:19]2=[O:20])=[N:23]1)#[N:38]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: C[C@@H](C(=O)N[C@H]1CNc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Product: CN[C@@H](C)C(=O)N[C@H]1CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)NC)C(=O)N(Cc4nn(-c5ccccc5C#N)c5ccccc45)c4ccccc43)cc2)c2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Product: Cl
Yield: 9.8 %

Procedure:
In a similar manner to that described for Example 22, ((S)-1-{(S)-1-[1-(2-cyano-phenyl)-1H-indazol-3-ylmethyl]-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (Intermediate 14) (262.9 mg, 0.443 mmol) and terephthaloyl chloride (45 mg, 0.222 mmol) were converted to the title compound (13 mg) as a white solid. LC-MS: 1118 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cn[nH]c2c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccc2cnn(CCOC3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 6-fluoro-1H-indazole (2.0 g, 14.7 mmol), and 2-(2-bromo-ethoxy)-tetrahydro-pyran (3.38 g, 16.2 mmol) in DMF (25 mL) was treated with caesium carbonate (6.1 g, 18.7 mmol) and stirred at RT for 18 h. The solvent volume was reduced in vacuo, and the residue partitioned between EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted into EtOAc (3×). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-50% cyclohexane in EtOAc, to afford the title product and a yellow oil. LCMS (Method 1): Rt 3.42 min, m/z 181 [MH+] (M-THP). 1H NMR (300 MHz; CDCl3) 1.52-1.56 (6 H, m), 3.39-3.49 (1 H, m), 3.57-3.68 (1 H, m), 3.89-3.91 (1 H, m), 4.19-4.21 (1 H, m), 4.56-4.57 (3 H, m), 6.88 (1 H, td, J 9.15 and 2.26), 7.30 (1 H, m), 7.62 (1 H, m), 8.04 (1 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([NH2:22])=[S:21])[CH2:15][CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:23]=1.[CH2:24]([O:26][C:27](=[O:45])[CH2:28][C:29](=O)[CH:30](Br)[CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH3:25].C1(C)C=CC=CC=1.C([OH:57])(C)(C)C>>[CH2:24]([O:26][C:27](=[O:45])[CH2:28][C:29]1[N:22]=[C:20]([CH2:19][N:16]2[CH2:17][CH2:18][N:13]([S:10]([C:8]3[S:7][C:6]4[CH:23]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH:9]=3)(=[O:11])=[O:12])[CH2:14][C:15]2=[O:57])[S:21][C:30]=1[CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH3:25]
Reactant: NC(=S)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Reactant: CCOC(=O)CC(=O)C(Br)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1nc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)sc1CNC(=O)OCc1ccccc1

Procedure:
A suspension of 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-thioacetamide (200 mg, 0.5 mmol) and 5-benzyloxycarbonylamino-4-bromo-3-oxo-pentanoic acid ethyl ester (370 mg, 1.0 mmol) is heated at 90° C. in a mixture of toluene/t-butanol, 1:1 (5 mL) for 16 h. The reaction is concentrated and purified using column chromatography (silica, 2%MeOH/CH2Cl2) to provide {5-(benzyloxycarbonylamino-methyl)-2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl}-acetic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ 7.87-7.81 (m, 3H), 7.45 (dd, 1H), 7.32 (s, 5H), 7.45 (bt, 1H), 5.07 (s, 2H), 4.73 (s, 2H), 4.42 (d, 2H), 4.13 (q, 2H), 3.90 (s, 2H), 3.76 (s, 2H), 3.61-3.55 (m, 2H), 3.50-3.43 (m, 2H), 1.24 (t, 3H); MS (ion spray) 677 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[F:11])[C:5]([OH:7])=O.[C:14](Cl)(=[O:17])[CH2:15][CH3:16].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([O:12][CH3:13])[C:10]([F:11])=[C:2]([NH:1][C:14](=[O:17])[CH2:15][CH3:16])[CH:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: CCC(=O)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1cc(C(=O)O)cc(N)c1F
Product: CCC(=O)Nc1cc(C(=O)Nc2cc(OC)c(OC)c(OC)c2)cc(OC)c1F

Procedure:
Compound 75 is synthesized following a similar method as in Example 1 and using 3-amino-4-fluoro-5-methoxybenzoic acid, propionyl chloride and 3,4,5-trimethoxyaniline as materials. Total yield of the two steps: 76%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C1C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(N)cn1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=Cc2cccc(Cl)c2)cn1

Procedure:
The starting material is prepared as follows: the mixture of 30.44 g of 5-aminopyridine-2-carboxylic acid methyl ester, 30.9 g of m-chlorobenzaldehyde, and 400 ml of benzene is refluxed for 3 days on a water-separating trap. The initial suspension eventually becomes a pale yellow solution, which is evaporated. The residual yellow solid is recrystallized from benzene-ethyl acetate-diethyl ether, to yield the 5-(m-chlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester melting at 139°-142°.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:8]=1)C.[Li+].[OH-].O.[CH2:31]1COCC1>CO>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[C:13]([CH:18]=1)[CH2:12][N:9]1[C:10]([CH3:31])=[CH:11][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:27])=[N:8]1
Reactant: CCOC(=O)COc1ccn(Cc2cc(Br)ccc2OCC(CC)CC)n1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)COc1ccc(Br)cc1Cn1nc(OCC(=O)O)cc1C
Temperature: 100 °C

Procedure:
To a solution of {1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazol-3-yloxy}-acetic acid ethyl ester, 4, (0.017 g, 0.038 mmol) in a mixture of THF (1 mL) and methanol (0.5 ml) was added a solution of LiOH (0.05 g in 1 ml H2O). The resulting mixture was heated at 100° C. in an Emrys microwave reactor for 15 minutes. The mixture was poured into water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (MgSO4) and the volatiles were removed in vacuo. The crude product was purified on silica to yield 0.016 g of {1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yloxy}-acetic acid, 5 as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([OH:40])=O)[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:75][CH2:76][CH2:77][NH:78][CH3:79]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:27])([CH3:28])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([N:78]([CH2:77][CH2:76][OH:75])[CH3:79])=[O:40])[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: CNCCO
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCC(CC(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCO)C(=O)CC1CCN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac {1-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (77 mg, 0.28 mmol) and DIPEA (94 uL, 0.54 mmol) were added followed by 2-hydroxy-ethyl-methyl amine (Oakwood, 20 mg, 0.27 mmol) and the mixture was stirred at rt overnight. The reaction was quenched with water and the mixture was extracted with methylene chloride (3×10 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 46 mg.