Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[N:8]=[CH:7]2)([O-:3])=[O:2].[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:7]2)([O-:3])=[O:2]
Reactant: BrCc1ccccn1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)CN(Cc1ccccn1)N2
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 5-nitroindazole (2 g, 12.3 mmol) in DMF (20 mL) was added K2CO3 (5.1 g, 36.8 mmol) and 2-(bromomethyl)-pyridine (2.2 g, 13.5 mmol). The resulting mixture was stirred at RT for 3.5 days, then poured into 100 mL of water. The resulting slurry was filtered, rinsed once with water and dried in vacuo giving a solid. The crude material was purified by chromatography (SiO2, elution with 3:1 EtOAc-hexanes followed by EtOAc followed by 7:1 CH2C2—MeOH) giving 5-nitro-1-pyridin-2-ylmethyl-1H-indazole and 5-nitro-2-pyridin-2-ylmethyl-1H-indazole.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]([NH2:14])=O)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([C:12]#[N:14])[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1nc(-c2ccccc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1nc(-c2ccccc2)c[nH]1
Temperature: -20 °C
Yield: 49.1 %

Procedure:
A suspension of 4.55 g of 4-phenyl-1H-imidazole-2-carboxamide in pyridine (30 ml) was stirred and cooled to -20° C. and treated dropwise with phosphorous oxychloride (2.3 ml) keeping the internal temperature below 0° C. After 40 min the reaction mixture was cooled to -25° C. and water (5 ml) was slowly added. The resultant suspension was poured into stirred water, carefully basified with potassium carbonate, and then filtered. The filtered solid was dissolved in dichloromethane and passed through a short column of fine silica. The column was eluted with dichloromethane-ethyl acetate (9:1), the appropriate fractions were collected and evaporated to give 4-phenyl-1H-imidazole-2-carbonitrile (2.02 g), which was treated in the manner as described in Example 3b and converted with methanesulphone acid into N-hydroxy-4-phenyl-1H-imidazole-2carboximidamide methanesulphonate (1:2), m.p. 151°-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](O)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][OH:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccc(Br)cc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
To a solution of 6-bromo-1H-indole-2-carboxylic acid (1.00 g, 4.20 mmol) in THF (20.0 mL) was added LiAlH4 (1.0 M in THF, 4.20 mL, 4.20 mmol) dropwise at 0° C. The reaction mixture was stirred for 4 h while warming to room temperature. The reaction was quenched with water and 15% aqueous NaOH at 0° C. to form a precipitate which was filtered through Celite. The filtrate was extracted with EtOAc (3×). The extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (696 mg, 73%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.51 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.20 (dd, J=8.0, 1.6 Hz, 1H), 6.38 (s, 1H), 4.83 (d, J=5.6 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:13]([O:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=1[CH3:11])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl-benzoic acid (1) (5.41 g, 32.5 mmol) in anhydrous pyridine (50 mL) were added acetic anhydride and 4-dimethylaminopyridine (0.1 g, 0.8 mmol). The reaction mixture was stirred at room temperature for 16 hours. Pyridine was evaporated under reduced pressure. The residue was taken in ethyl acetate (300 mL). The organic phase was washed with 2 N aq. HCl (100 mL), water (2×100 mL), brine (100 mL) and dried over anhydrous Na2SO4. Solvent was evaporated to give 4-acetoxy-3,5-dimethylbenzoic acid (2) as an off-white solid. Yield: 6.65 g (98%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][C:32](=[O:34])[CH3:33].[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1)[C:32](=[O:34])[CH3:33]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2ccccn2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 9.4 g of product from Example 20, 3.87 g of product from Example 12, 1.24 g of 50% sodium hydride and 130 ml of dry tetrahydrofuran. The reaction is stirred at room temperature for 31/2 hours. The residue is purified by column chromatography (silica gel:60-100% ethyl acetate/hexane) to give 9.42 g of the desired product as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C@@H:43]([OH:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[H-].[K+].[CH3:48][N:49]([CH3:53])[C:50](Cl)=[O:51]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][C@@H:43]([O:45][C:50](=[O:51])[N:49]([CH3:53])[CH3:48])[CH3:44])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@H](C)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@H](C)OC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
To a solution of 100 mg of (S)-1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propan-2-ol (diastereomer 2) (from example 34b) in 10 ml tetrahydrofuran are added 34 mg of potassium hydride and 0.14 ml of N,N-dimethylcarbamoyl chloride at room temperature. The reaction mixture is stirred for one additional hour, diluted with water and extracted with tert-butyl methyl ether. The combined organic phases are dried and concentrated under reduced pressure to afford the crude title compound. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.41 (EtOAc-heptane 2:1); Rt=5.47.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]=[CH:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]([CH2:21][CH3:22])[CH3:20])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:23])=[N:4][CH:3]=1.C(Cl)Cl.CO>[Pd].CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]([CH2:21][CH3:22])[CH3:20])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:23])=[N:4][CH:3]=1
Reactant: CCN(C)c1nc(C=Cc2nc3c(C)ncc(C)n3n2)n(C)n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCN(C)c1nc(CCc2nc3c(C)ncc(C)n3n2)n(C)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.7 %

Procedure:
A mixture of 5-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-N-ethyl-N,1-dimethyl-1H-1,2,4-triazol-3-amine (7 mg, 22.4 μmol, Eq: 1.00) and palladium on carbon 10% (4.77 mg, 4.48 μmol, Eq: 0.2) in methanol (1 ml) was stirred for 14 hours at 25° C. under hydrogen atmosphere. TLC (CH2Cl2/MeOH 19:1/UV 254 nm) showed complete reaction (spot to spot). palladium was filtered off and the filtrate was evaporated and applied on silica gel. Purification by column chromatography over 10 g SiO2 using ethyl acetate/methanol (0-10% MeOH) as eluent to give {5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-ethyl-methyl-amine (3.5 mg, 49.7%) as off-white solid
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:39])=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].NC1C=CC(C(N2CCCC2)=[O:53])=CC=1>>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:53])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:39])=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Nc3ccc(C(=O)N4CCCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 59 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-{4-(pyrrolidine-1-carbonyl)phenylamino}benzonitrile was prepared using compound (6d) instead of compound (1e) and using (4-aminophenyl)(pyrrolidin-1-yl)methanone instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (34) (the second stage yield: 59%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-{4-(pyrrolidine-1-carbonyl)phenylamino}benzonitrile instead of compound (1f).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:17])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2nccnc2c1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of quinoxaline-6-carboxylic acid (438 mg, 2.51 mmol) in benzene (16 mL) was added oxalyl chloride (0.26 mL, 3.02 mmol) and anhydrous DMF (0.1 mL). The reaction was stirred at room temperature for 30 minutes after which the mixture was concentrated in vacuo. The resulting yellow solid was azeotroped 3× with toluene and the product was used immediately without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH2:14][C@@H:10]([C:11]([OH:13])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:18]1([NH:17][C:11]([C@@H:10]2[CH2:14][CH2:15][CH2:16][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]2)=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of N-Boc-(R)-nipecotic acid 25 (4.00 g, 17.5 mmol) and aniline (1.67 mL, 1.05 eq.) in 30 mL of dry CH2Cl2 was added DCC (4.88 g, 1.05 eq.) in one portion at 0° C. The mixture was stirred at room temperature for 4 hours. Filtration and removal of the solvent gave an oily crude product, which was purified by flash column chromatography (silica gel, hexane:ethyl acetate) to afford (R)-1-Boc-piperidine-3-carboxylic acid phenyl amide 26 as a colorless oil (5.26 g, 99%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:24]=3)[CH:15]=[CH:14][N:10]2[C:11](=[O:13])[CH:12]=1)(=O)=O.B1([C:36]2[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=2)OCCCO1.[Br-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[CH:25]([C:23]1[N:24]=[C:20]([CH2:19][CH2:18][C:16]2[CH:15]=[CH:14][N:10]3[C:11](=[O:13])[CH:12]=[C:7]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[N:8]=[C:9]3[CH:17]=2)[S:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)cc(OS(=O)(=O)C(F)(F)F)nc3c2)n1
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)c1csc(CCc2ccn3c(=O)cc(-c4cccnc4)nc3c2)n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
2-Trifluoromethanesulfonyloxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one(499 mg), pyridine-3-boronic acid 1,3-propanediol cyclic ester (364 mg), palladium tetrakistriphenylphosphine (65 mg), potassium bromide (146 mg) and potassium carbonate (231 mg) were added with dioxane(8 ml) and stirred overnight at 85° C. under nitrogen atmosphere. The reaction mixture was cooled and then added with ethyl acetate. Insoluble solids were removed by filtration, and the solvent of the filtrate was evaporated. The residue was purified by silica gel column chromatography to obtain the title compound (400 mg).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])(=[O:19])=[O:18].[CH2:30]([C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH2:31][CH3:32]>>[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:36]3[CH:38]=[CH:39][C:33]([CH2:30][CH2:31][CH3:32])=[CH:34][CH:35]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:28])=[O:27])(=[O:19])=[O:18]
Reactant: CCCc1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4S(C)(=O)=O)CC3)C2=O)cc1

Procedure:
White solid. MS (ESI): 491.16 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methanesulfonyl-benzenesulfonyl chloride and 4-propyl-aniline.
Reaction SMILES: ClC1[CH:3]=[CH:4][C:5]([NH:16][CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:27]([Cl:29])Cl>>[C:7]([C:6]1[CH:15]=[C:27]([Cl:29])[CH:3]=[CH:4][C:5]=1[N:16]([CH3:17])[C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26])(=[O:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C=Nc1ccccc1
Reactant: ClCCl
Product: CN(C(=O)Nc1ccccc1)c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 66 %

Procedure:
A solution of 12.3 g (0.05 mole) of 5-chloro-2-methylaminobenzophenone and 11.9 g (0.1 mole) of phenyl isocyanate in 50 ml of methylene chloride was refluxed for 3 days, and then evaporated to dryness under reduced pressure. The residual syrup was stirred with ether until it crystallized. The crystals were collected on a filter and washed with ether to give 12.06 g (66%) of 1-(2-benzoyl-4-chlorophenyl)-1-methyl-3-phenylurea as light yellow crystals. A sample was recrystallized from ethanol to give colorless crystals: mp 158°-160°; 1H nmr (DMSO-d6) δ3.41 ppm (s, 3H), 6.7-7.5 ppm (m, 13H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1ccc(N)nc1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 300 mg, 0.84 mmol) and triphenylphosphine (288 mg, 1.09 mmol) in methylene chloride (6.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (192 mg, 1.09 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-picoline (182 mg, 1.68 mmol) and 2,6-lutidine (0.42 mL, 3.36 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 4/6 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (231 mg, 61%) as a white foam: [α]23589=−26.22° (c=0.45, chloroform); EI-HRMS m/e calcd for C22H25ClN2O4S (M+H)+ 449.1297. found 449.1302.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:18]=[N-:19].CO.C[O-].[Na+].[OH-].[Na+]>CO>[C:20]1([N:17]2[C:2]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:3]([C:4]([OH:6])=[O:5])[N:19]=[N:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nnn(-c2ccccc2)c1CCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A solution of ethyl 3-oxo-5-phenylpentanoate (1.1 g) in methanol (50 ml) was cooled to 0° C.-5° C., azidobenzene (600 mg) and 28% sodium methoxide methanol solution (965 mg) were added and the mixture was stirred at 60° C. for 3 hr. Then, 1N sodium hydroxide (10 ml) was added and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure and water (20 ml) was added. 1N Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate (30 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (480 mg) as a powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)=[C:8]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].O[Li].O>C1COCC1.CO.O>[CH:10]([C:9]1[C:8]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])=[C:7]([C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])([CH3:11])[CH3:12]
Reactant: COC(=O)c1sc(-c2cccc(C)c2)c(NC(=O)C2CCC(C)CC2)c1C(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(-c2sc(C(=O)O)c(C(C)C)c2NC(=O)C2CCC(C)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.4 %

Procedure:
3-Isopropyl-[(4-methyl-cyclohexanecarbonyl)-amino]-5-m-tolyl-thiophene-2-carboxylic acid methyl ester (30 mg, 0.073 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then added 1N aqueous solution of LiOH.H2O (0.44 mL, 0.438 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4)— and concentrated. The residue was purified by preparative TLC using chloroform:methanol:acetic acid (9:1:0.1) to obtain 3-Isopropyl-[(4-methyl-cyclohexanecarbonyl)-amino]-5-m-tolyl-thiophene-2-carboxylic acid (15 mg, 52%) as a white solid. 1H NMR (CDCl3, 400 MHz): (s, 2H), 7.38 (t, 1H), 7.24 (m, 1H), 7.08 (s, 1H), 5.01 (s, 1H), 2.42 (s, 3H), 2.10-0.62 (m, 20H). ESI− (M-H): 398.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[CH2:34][N:35]([CH3:37])[CH3:36])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[I:40][CH3:41]>C1C=CC=CC=1>[I-:40].[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[CH2:34][N+:35]([CH3:41])([CH3:36])[CH3:37])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CI
Reactant: C[C@@H](O[C@H]1CN(C2=C(CN(C)C)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccccc1
Product: C[C@@H](O[C@H]1CN(C2=C(C[N+](C)(C)C)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: [I-]
Temperature: 60 °C

Procedure:
In a pressure tube, 22 mg (0.0394 mmol) 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-2-[(dimethylamino)methyl]cyclopent-2-en-1-one (step A), and 0.025 mL (0.3939 mmol) iodomethane was dissolved in benzene (1 mL). The tube was sealed and heated in an oil bath for 2.5 hr at ˜60° C. The reaction mixture was cooled to RT, the tube was opened and the solvent removed under vacuum to afford the title compound as a yellow oil which was used in the next reaction without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[C:18]([Cl:25])[CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:25].[ClH:25].[Cl:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH:24]=[CH:23]2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc3cccc(Cl)c3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cccc2ccc(NC3CCNCC3)nc12

Procedure:
A solution of 4-(8-chloro-quinolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.30 g, 3.59 mmol) in 4 M HCl in dioxane (120 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 262.3 [M+H]+.