Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].[C:34]([O:38][C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:46]2[CH:47]=[CH:48][C:43]([CH2:42][NH:41][C:39](=[O:40])[O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:44][CH:45]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.250 g, 1 eq.) in a mixture of toluene (5 mL), ethanol (5 mL), and saturated sodium bicarbonate (1 mL) was added (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (0.1 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.025 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl 4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)benzylcarbamate (0.133 g, 40%). LCMS: 516 [M+H].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.OP([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 40 h
Yield: 67.4 %

Procedure:
A mixture of 2-chloro-4-methyl-3-nitropyridine (28; 1.08 g, 6.24 mmol), 2,4-dichlorophenyl boronic acid (1.26 g, 6.62 mmol), (Ph3P)4Pd(0) (0.405 g, 0.350 mmol), 40 mL of DMF, and 20 mL of a 2 M aqueous K2HPO4 solution was stirred at 70° C. for 40 h. The mixture was partitioned between 200 mL of diethyl ether and 200 mL of water. The organic layer was sequentially washed with 200 mL of water and 200 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a yellow oil mixed with white solid. Column chromatography (0→20% EtOAc/hexanes) afforded slightly impure 2-(2,4-dichloro-phenyl)4-methyl-3-nitro-pyridine (29; 1.19 g; 68%) as a yellow oil that was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH:8]=O)[C:3]([O:5]CC)=O.Cl.[CH2:11]([NH:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([N:18]1[C:3]([OH:5])=[C:2]([CH3:1])[CH:8]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNCc1ccccc1
Reactant: CCOC(=O)C(C)C=O
Agent: Cl
Solvent: CCO
Product: Cc1cnn(Cc2ccccc2)c1O
Temperature: 80 °C
Reaction time: 5 h
Yield: 59.5 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 2-methyl-3-oxopropanoate (compound 249.1, 500 mg, 3.84 mmol) in ethanol (15 mL). Benzylhydrazine hydrochloride (730 mg, 4.66 mmol) was added and the reaction was stirred for 5 h at 80° C., then concentrated under reduced pressure. The residue was purified by a silica gel chromatography with dichloromethane/methanol (30:1) as eluent to obtain the title compound as a yellow oil (430 mg, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:13]1[C:21]2[C:20]([NH:22][C@H:23]([C:25]3[N:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:29](=[O:37])[C:28]4=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]4[N:26]=3)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=2[N:15](COCC[Si](C)(C)C)[CH:14]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:4][C:3]=1[C:13]1[C:21]2[C:20]([NH:22][C@H:23]([C:25]3[N:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:29](=[O:37])[C:28]4=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]4[N:26]=3)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)ccc3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(C)(=O)=O)ccc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 30.4 %

Procedure:
(S)—N-(4-Hydroxy-3-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (102 mg, 0.15 mmol) was treated with trifluoroacetic acid (2.7 ml, 35.05 mmol) and a solution of ammonia (7N in methanol, 2.7 ml, 19 mmol) according to the method described in Example 27 to give 26 mg (29% yield) of the title compound. Purity 93%.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Methyl 4-[N-(3-phenyl-1H-indazole-5-yl)carbamoyl]benzoate (92 mg, 0.247 mmol) was added to a solution of lithium hydroxide (10 mg, 1.23 mmol) in tetrahydrofuran (5 mL) and water (5 mL). The solution was allowed to stir at room temperature for 3 hours. The solution was acidified using a 5% HCl solution. The resulting white precipitate was filtered and dried to provide the title compound (62 mg, 70% yield). 1H NMR (DMSO-d6) δ 13.22 (br s, 1H), 10.48 (s, 1H), 8.55 (s, 1H), 8.06 (s, 4H), 7.92 (d, 2H), 7.75 (d, 1H), 7.55 (m, 3H), 7.38 (m, 1H); ES-MS (m/z) 358 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.2 %

Procedure:
tert-Butyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 2, 1.978 g, 5.257 mol) was treated with 4 M HCl in dioxane (20 ml), and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to give the desired material as a pink solid (1.61 g, 98% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:7]=[CH:8][CH2:9][CH:10]=1)[C:4]([OH:6])=[O:5]>C1C2C(CCCC2)CCC1.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC1=CCC=CC1C(=O)O
Agent: *O[SiH2]*
Solvent: CCCCCC
Solvent: C1CCC2CCCCC2C1
Product: Cc1ccccc1C(=O)O
Yield: 95.5 %

Procedure:
To a suspension of 2-methyl-l,4-dihydrobenzoic acid (0.085 g, 0.50 mmol; 81% pure, from Aldrich Chemical Company) in decalin (5 mL) under a nitrogen atmosphere was added the polysiloxane matrix material containing a homogeneous dispersion of metal particles (0.100 g as prepared according to Example 1). The solution was heated to reflux for 19 hours. On cooling the reaction mixture was diluted with hexane (25 mL) and extracted with aqueous sodium hydroxide (5%) solution (2×5 mL). The basic aqueous solution was acidified and extracted with chloroform (3×4 mL). The combined organic layer was dried over anhydrous sodium sulfate. Removal of solvent on rotary evaporator gave 2-methylbenzoic acid (0.065 g. 96%). IR(KBr) 3600-2000 (br), 2923, 1694, 1300, 920,731 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.03 (ddd, J=8.5, 3.0, 1.5 Hz, 1 H), 7.42 (td, J=8.5, 1.5 Hz, 1H), 7.26 (td, J=8.5, 1.5 Hz, 1 H), 7.22 (dd, J=8.5, 1.5 Hz, 1 H), 2.64 (s, 3H).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:2]([C:7]([N:9]2[CH2:13][C@H:12](O)[CH2:11][C@H:10]2[CH2:15][NH:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)=[O:18])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.COCCN(S(F)(F)[F:45])CCOC>C(Cl)Cl>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:2]([C:7]([N:9]2[CH2:13][C@@H:12]([F:45])[CH2:11][C@H:10]2[CH2:15][NH:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)=[O:18])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-(((2S,4R)-1-(biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)quinoline-8-carboxamide (0.045 g, 0.10 mmol) in DCM was cooled to −78° C., added with bis(2-methoxyethyl)aminosulfur trifluoride (Aldrich) (41 μL, 0.22 mmol) dropwise. The resulting solution was stirred at −78° C. for 0.5 h, allowed to warm to rt gradually over 1.5 h and stirred at rt for 0.5 h, which was quenched by slow addition of MeOH and purified by preparative HPLC using acetonitrile and water (0.1% TFA) as eluent to provide N-(((2S,4S)-1-(biphenylcarbonyl)-4-fluoropyrrolidin-2-yl)methyl)quinoline-8-carboxamide as a white solid. MS (ESI) 454.14 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].CI.[C:22](=O)([O-])O.[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of ethyl 2-(3-chloro-4-nitrophenyl)propanoate (14.1 g) is added dropwise to a suspension of sodium hydride (60% in oil, 2.4 g, 1.1 eq) in DMF (15 ml), cooled down to 0° C. After stirring for 1 hour at this temperature, a solution of methyl iodide (3.72 ml, 1.1 eq) in DMF (40 ml) is added dropwise to the mixture. Stirring is continued for 3 hours at ambient temperature. The reaction medium is cooled down to 0° C. then ethyl acetate, water saturated with sodium hydrogen carbonate, then water are added dropwise. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure in order to produce the expected compound in the form of an oil which crystallizes. The crystals are washed with heptane and dried (13.8 g; 94% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH:3]=1.O.[NH2:23][NH2:24]>O1CCCC1>[NH:23]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH:3]=1)[NH2:24]
Reactant: NN
Reactant: Cc1nc(Cl)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(NN)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1

Procedure:
A solution of 2-((1R,2R)-2-(6-chloro-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (4-6, 200 mg, 0.0.669 mmol, 1.0 eq) and hydrazine hydrate (335 mg, 6.69 mmol, 10 eq) in tetrahydrofuran (3 mL) was heated by microwave irradiation at 80° C. for 40 minutes. The reaction mixture was filtered and concentrated to dryness. The afford 2-((1R,2R)-2-(6-hydrazinyl-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (4-7) as a glassy yellow solid. LRMS m/z (M+H) 294.4 found, 294.2 required.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:34]=[CH:33][C:10]2[N:11]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31][CH3:32])[CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[C:12](=[O:14])[O:13][C:9]=2[CH:8]=1)C.Cl>C1COCC1.[OH-].[Na+]>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16](=[O:17])[CH2:15][N:11]3[C:10]4[CH:33]=[CH:34][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[CH:8][C:9]=4[O:13][C:12]3=[O:14])[CH2:23][CH2:22]2)=[CH:25][C:26]=1[O:31][CH3:32]
Reactant: CCOC(=O)COc1ccc2c(c1)oc(=O)n2CC(=O)N1CCN(c2ccc(Cl)c(OC)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(OCC(=O)O)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid ethyl ester (45) in THF (3 ml) and NaOH (2N, 3 ml) was stirred at rt for 2 hours. The reaction mixture was neutralized with HCl (1 N), extracted with ethyl acetate, washed with water, and purified by flash chromatography to provide (3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid (46): LCMS observed for (M+H)+: 476.5
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f13) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[C@@H:17]([O:24][CH3:25])[CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:25][O:24][C@H:17]1[CH2:16][C@@H:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][CH2:19][C@@H:18]1[CH2:21][C:22]#[N:23]
Reactant: CO[C@H]1C[C@@H](N)CC[C@@H]1CC#N
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CO[C@H]1C[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC[C@@H]1CC#N
Temperature: 90 °C
Yield: 76.1 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (381 mg, 1.78 mmol), [(1R,2S,4S)-4-amino-2-methoxycyclohexyl]acetonitrile (racemic) (310 mg, 1.8 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.1 mmol) in isopropyl alcohol (4.2 mL) was heated at 90° C. for 2 h. The crude was concentrated and purified with flash chromatography to give the desired product (469 mg, 76%). LCMS calculated for C15H19N4O3S (M+H)+: m/z=347.1. Found: 347.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].ClC1C=CC(Cl)=CC=1Cl.[Cl-].[Cl-].[Cl-].[Al+3]>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: CCC(=O)c1ccc(NC(C)=O)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
Acetanilide (13.94 g), propionyl chloride (14.31 g) and 1,2,4-trichlorobenzene (100 ml) were warmed to 60° C. and aluminium trichloride (40.0 g) was added over 15 minutes. The mixture was heated at 100° C. for 90 minutes, cooled at 40° C. and ethanol (200 ml) was added dropwise keeping the temperature below 60° C. by means of an ice-water bath. After stirring for 30 minutes at 40° C. a homogeneous system was obtained. This was quenched with water (100 ml) at 25°-30° C. and stirred for 15 minutes. Dichloromethane (300 ml) and water (200 ml) were added and the organic layer was separated and washed with water (2×200 ml). The organic layer was evaporated to about half-volume (about 150 ml), and petroleum ether (60° C.-80° C.) (150 ml) was added at 50° C. A solid precipitated and was collected after 60 minutes of stirring to afford p-acetamidopropiophenone (15.12 g; 79%), m.p. 169°-70° C.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:12]([CH3:25])[C:11]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[C:36]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:37]([O:39]CC)=[O:38].[OH-].[Na+]>CC(O)(C)C>[C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:36]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:37]([OH:39])=[O:38])=[CH:22][CH:23]=3)[N:12]([CH3:25])[C:11]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCCc1ccc(O)cc1
Reactant: CCOC(=O)C(Br)(CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCC(CC)(Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1)C(=O)O
Temperature: 100 °C
Yield: 14 %

Procedure:
A mixture of 1-(4-tert-butyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.077 g, 0.202 mmol), potassium tert-butoxide (0.091 g, 0.745 mmol) and ethyl α-bromodiethylacetate (0.361 g, 1.61 mmol) in 2-methyl-2-propanol (8 mL) was heated to 100° C. under N2 for 16 h. Aqueous 5 N NaOH (1.5 mL) was added to the reaction mixture and it was heated at reflux an additional 1 h. The reaction mixture was cooled and quenched with 1 N HCl. The mixture was then diluted with water and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.288 g of crude product that was purified by preparative HPLC to give 0.014 g (14%) 2-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-ethyl-butyric acid. 1H NMR. HRMS (ES+) m/z exact mass calcd for C30H43N2O4 [M+1] 495.3223, found 495.3252.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1.[C:32]([Mg]Br)#[CH:33]>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:32]#[CH:33])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Cl)c2=O)c1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Cl)c2=O)c1

Procedure:
To a solution of 3-[5-chloro-2-methyl-4-(6-methyl-pyridin-2-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step B (73 mg, 0.16 mmol) in tetrahydrofuran (2 mL), cooled using an ice water bath, was added ethynylmagnesium bromide, 0.5M in tetrahydrofuran, (0.5 mL, 0.25 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without any additional purification.
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH:8]([CH2:10][O:11]C(=O)C)[CH2:7][CH:6]1[N:15]1[C:19]2[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:18]=2[N:17]=[C:16]1[Br:26])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.CO>O.C(O)(=O)C>[Br:26][C:16]1[N:15]([CH:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][CH:5]2[OH:4])[C:19]2[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:18]=2[N:17]=1
Reactant: CC(=O)OCC1CC(OC(C)=O)C(n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: OCC1CC(O)C(n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Reaction time: 2 h
Yield: 72 %

Procedure:
(±)-(1R*, 2R*,4S*)-4-(Acetoxymethyl)-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-cyclopentyl acetate (2.75 g, 5.92 mmol) was added to a stirred mixture of sodium carbonate (0.63 g) in water (11 mL)-ethanol (55 mL)-methanol (55 mL). After 2 hours at ambient temperature, the pH was adjusted to 7 with glacial acetic acid. Volatiles were removed in vacuo and the residue triturated with water (30 mL) and filtered to give white solid. Recrystallization of the solid from 1:1 ethanol-methanol gave title compound as white powder (1.62 g, 72%), m.p. 218°-220° C.; 1H-NMR (DMSO-d6)δ: 8.18 (s, 1, benzimidazole H7), 7.97 (s, 1, benzimidazole H4), 5.20 (m, 1, OH), 4.95 (m, 1, OH), 4.80-4.60 (m, 2, OCH and NCH), 3.50-3.40 (m, 2, OCH2), 2.45-2.20 (m, 1, CH), 2.20-1.60 (m, 4, 4CH); mass spectrum (CI): 379 (M+1).
Reaction SMILES: C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.CCN(CC)CC.[C:34]([NH:38][CH2:39][C:40]1[CH:49]=[C:48]2[C:43]([C:44](=[O:50])[CH2:45][CH2:46][O:47]2)=[CH:42][C:41]=1[Cl:51])([CH3:37])([CH3:36])[CH3:35]>CC(O)C.CC#N.CCCCCC.CCOCC>[C:34]([NH:38][CH2:39][C:40]1[CH:49]=[C:48]2[C:43]([C@@H:44]([OH:50])[CH2:45][CH2:46][O:47]2)=[CH:42][C:41]=1[Cl:51])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NCc1cc2c(cc1Cl)C(=O)CCO2
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)NCc1cc2c(cc1Cl)[C@@H](O)CCO2
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (1S,2S)-(+)-N-(4-toluene-sulfonyl)-1,2-diphenylethylenediamine (0.29 g, 8.08 mmol) in i-PrOH (15 mL) was added [RuCl2(n6-p-cymene)]2, and Et3N under argon. The mixture was heated at 80° C. for 1 h, cooled, and concentrated to dryness. To this mixture was added a solution of 7-(tert-butylamino-methyl)-6-chloro-chroman-4-one (12 g, 44.91 mole) in anhydrous CH3CN (150 mL), followed by 5:2 formic acid/TEA (6 mL). The reaction was stirred at RT for 24 h. The mixture was concentrated, taken up in H2O, neutralized with 10% Na2CO3, extracted with CH2Cl2 (3×), dried over MgSO4, concentrated to give a brown foam which was stirred in hexane/ether (1:1), and filtered. The filtrate was concentrated to give a light brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4]O.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[Cl:13][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(Cl)c1CO
Solvent: c1ccccc1
Product: Cc1cccc(Cl)c1CCl

Procedure:
The 2-chloro-6-methylbenzyl alcohol is dissolved in 100 ml of benzene, treated with 25 ml of thionyl chloride and the mixture is heated at reflux for 3 hours. Concentration of this mixture to dryness leaves a liquid which partly solidifies. The product containing liquid is decanted from the solid by-product and distilled to yield 7.8 g of alpha,2-dichloro-6-methyltoluene as a colorless liquid with bp. 118°-122° C./17-18 mm of Hg.