Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1(N=C=NC2CCCCC2)CCCC[CH2:12]1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction mixture of 2-chloropyrimidine-4-carboxylic acid, 9.A (avialable from Anichem LLC, 1.00 g, 6.3 mmol), 1,3-dicyclohexylcarbodiimide (1.4 g, 6.9 mmol) and ethanol (0.32 g, 6.9 mmol) in DCM (10 ml) was stirred at room temperature overnight. The solid was filtrated off. DCM (80 ml) was added and washed with brine (30 ml) and dried over MgSO4. The solvent was evaporated. The crude product was purified by Cobi-Flash silica gel column to give 9.B. 0.74 g, yield, 63%. 1H NMR (400 MHz, chloroform-d) δ ppm 8.87 (1H, d, J=4.7 Hz), 7.95 (1H, d, J=4.7 Hz), 4.51 (2H, q, J=7.4 Hz), 1.45 (3H, t, J=7.0 Hz). MS ESI (pos.) m/e: 187.0 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.Cl.Cl.Cl.N1C=C(C[N:15]2[C:21]3[CH:22]=CC(C4C=NC=CC=4)=[CH:25][C:20]=3[CH2:19][N:18]([C:32](=[O:37])[C:33](F)(F)F)[CH:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:16]2)N=C1>C(Cl)Cl.O>[C:16]([C:17]1[CH:38]=[CH:22][C:21]2[NH:15][CH2:16][C@@H:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:18]([C:32](=[O:37])[CH2:33][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:19][C:20]=2[CH:25]=1)#[N:15]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Temperature: 25 °C
Reaction time: 16 h
Yield: 151.8 %

Procedure:
Methanesulfonyl chloride (3.68 mL, 47.6 mmol) was added dropwise as a solution in CH2Cl2 (20 mL) to a solution of Compound B (10 g, 36.6 mmol) in CH2Cl2 (130 mL) at 0° C. under argon. After stirring at rt for 16 hr the reaction was diluted with water (20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×40 mL). The combined organic layers were washed with water (1×30 mL), KHSO4 (2×30 mL), water (1×30 mL), NaHCO3 (2×30 mL), brine (1×30 mL), dried over MgSO4, filtered and concentrated to afford a golden brown oil. The oil was crystalized from EtOAc/hexanes and the yellow solid triturated with hexane and dried to afford Compound C (10.6 g, 82 %). MS: [M+H]+ =351
Reaction SMILES: Br([O-])(=O)=O.[Na+].[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.CC[O:17]CC>C(#N)C.O>[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:17])=[O:12])=[CH:9][CH:8]=1
Reactant: CCOCC
Reactant: Cc1ccc(CO)cc1
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 96 %

Procedure:
A mixture of Ceiv catalyst from Example 47 (0.08 g), sodium bromate (0.3 g) and 4-methylbenzyl alcohol (0.24 g, 2 mmol) in acetonitrile:water (1:1, 10 ml) was stirred at 80° C. for 40 h under an atmosphere of nitrogen. On cooling ether (70 ml) was added and the catalyst was filtered off. The organic layer was separated and the aqueous phase was extracted with ether (2×50 ml). The combined organic extracts were washed with water (25 ml), dried with anhydrous magnesium sulphate and concentrated to give 4-methylbenzoic acid as a white solid (0.26 g, 96%). M.p. 178° C., lit. 180-182° C.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30]C)=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:27][O:26][C:25]1[C:3](=[O:2])[C:4]([CH3:32])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:23](=[O:30])[C:24]=1[O:28][CH3:29]
Reactant: COc1c(C)c(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Yield: 48.8 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-phenoxybenzoic acid (0.220 g, 0.502 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.688 g, 1.26 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.100 g, 0.245 mmol, 49%).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH+:6]=[CH:5][CH:4]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:6]1[CH:7]=[CH:8][C:3]([N:10]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=[N:9]2)=[CH:4][CH:5]=1
Reactant: Clc1cc[nH+]cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2nn(-c3ccncc3)nc2c1
Temperature: 130 °C

Procedure:
A mixture of 4-chloropyridinium hydrochloride (25.0 g, 166 mmol), benzotriazole (29.6 g, 249 mmol), potassium carbonate (69.1 g, 500 mmol), and dimethylformamide (DMF) (500 mL) was stirred and heated under argon at 130° C. for 3 days. After cooling, the solid was filtered off, and the solvent was evaporated under reduced pressure. The residue was treated with dichloromethane (200 mL), filtered and chromatographed using a column filled with silica gel (500 mL) and hexane/ethyl acetate (1:1) as an eluent. Fractions containing the desired product were combined, and the solvent was distilled off. The residue was triturated with ethanol, the solid was filtered off and dried in a vacuum oven to give 2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole, 6.45 g, 20%). 1H NMR (400 MHz, CDCl3): δ 8.80 (m, 2H, pyridine), 8.26 (m, 2H, pyridine), 7.93 (m, 2H, benzotriazole), 7.46 (m, 2H, benzotriazole).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38])#[N:31].C(=O)([O-])[O-].[Na+].[Na+].O>C1COCC1.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>[Cl:13][C:11]1[CH:12]=[C:7]([C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([C:30]#[N:31])[CH:33]=2)[CH:8]=[C:9]([Cl:27])[C:10]=1[CH2:14][CH:15]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:16]1=[O:26]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
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: O
Solvent: C1CCOC1
Product: N#Cc1cc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)ccc1F
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 87.3 %

Procedure:
To a solution of 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.34 g, 2.83 mmol) in THF (30 mL) in a round bottom flask was added 3-cyano-4-fluorophenylboronic acid (560 mg, 3.39 mmol), sodium carbonate (900 mg, 8.48 mmol) and water (10 mL). The mixture was stirred at 60° C. for 5 minutes, palladium tetrakis (163 mg, 0.14 mmol) was added. Reaction mixture was brought to 80° C. and stirred for 3 hours. Cooled and partitioned between ethyl acetate and HCL(1 N). Organic was separated, wash with water, brine; dry over sodium sulfate, filter, and concentrate. Purify by silica gel (25-50% ethyl acetate in hexane) to afford 1.10 g (88%) of the title compound: Mass spectrum (LCMS) m/z=445.0 (M+H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]([C:33]4[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=4)[C:36]([O:38]CC)=[O:37])[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)[N:10]=[N:9]2)C=CC=CC=1.[OH-].[Li+]>C(O)(=O)C.O.O1CCOCC1.O>[NH:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[CH:21][C:22]([CH2:25][N:26]([C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36]([OH:38])=[O:37])[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:24]=2)=[N:12][N:8]=[N:9]1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1)c1cccc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
Ethyl 3-[N-[[4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methyl]-N-pentanoylamino]benzoate (0.37 g) synthesized in Example 1a was dissolved in 75% acetic acid-water (8.8 ml), and the mixture was stirred at room temperature for 24 hrs. The reaction mixture was concentrated and dried to give a solid. The residue was dissolved in 75% dioxane-water (8.8 ml), lithium hydroxide (45 mg) was added, and the mixture was stirred at 50° C. for 24 hrs. The reaction mixture was concentrated to give a solid, and the residue was purified by silica gel column chromatography (methylene chloride-methanol:7-3 v/v) to give the object compound (0.12 g, yield 88%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.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:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:45])=[O:46])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 25.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.266 g, 0.99 mmol), tetrakis(triphenylphosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (130 mg, 25%). MS (ISP) 590.4 [(M+H)+]; mp 260° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[CH3:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][CH:14]([OH:15])[CH3:16])=[CH:6][CH:5]=1
Reactant: CC1CO1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc2ccn(CC(C)O)c2c1
Reaction time: 1 h
Yield: 35 %

Procedure:
A suspension of 0.28 g of sodium hydride dispersion in 40 ml of tetrahydrofuran was treated with 0.98 g of 6-methylindole at 0° and stirred at this temperature for 1 hour. After the addition of 1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 60 hours and subsequently treated with 7 ml of water. The mixture was diluted with 370 ml of ether, washed twice with 120 ml of water and with 60 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 35 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.5 g (35%) of (RS)-1-(6-methyl-indol-1-yl)-propan-2-ol as light brown crystals with m.p. 65°-69°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccccc1-c1ccc(Cl)nn1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 3-chloro-6-phenylpyridazine (Aldrich, 1.4 g, 7.5 mmol) in conc. sulfuric acid (30 mL) was added 90% nitric acid (0.6 mL, 15 mmol). After 15 min. the mixture was poured over ice (200 mL) and neutralized with 25% aq. NaOH. The resulting precipitate was collected by filtration and dried under vacuum. The crude product (1.84 g) was a 1:1:0.5 mixture of ortho:meta:para isomers.
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.[C:16]([CH2:20][C:21](Cl)=[O:22])([CH3:19])([CH3:18])[CH3:17].[F:24][C:25]([F:35])([F:34])[CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:20][C:21]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:31]([C:30]3[CH:32]=[CH:33][C:27]([CH2:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)=[O:22]
Reactant: Nc1ccc(CC(F)(F)F)cc1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(CC(F)(F)F)cc1)C2=O

Procedure:
Off-white solid. MS (ESI): 411.22 (MH+). This example was prepared in analogy to example 7 step A) to B) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), tert.-butylacetyl chloride and 4-(2,2,2-trifluoroethyl)-aniline.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[OH:7][C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)CC1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
To a solution of 1,4-cyclohexanedione (6.72 g, 60 mmol) in THF (100 mL) cooled in an ice bath was added a 1 M solution of phenyl magnesium bromide in THF (20 mL, 20 mmol). The mixture was stirred at room temperature for 3 hours and quenched with an NH4Cl solution. The resulting solution was extracted with EtOAc three times. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 1:1 EtOAc/hexanes yielded 0.83 g (22%) of the title compound. MS calculated (M+H)+ 190. found 173 (M+H−H2O)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:24][NH2:25].O>O1CCOCC1>[N:8]1([C:6]2[N:5]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:16]=[C:4]3[N:3]=[C:2]([NH:24][NH2:25])[CH:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 90 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To a solution of 5-chloro-7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidine (150 mg, 0.48 mM) in 1,4-dioxane (5.0 mL), there was added hydrazine monohydrate (0.23 mL, 4.8 mM) and the mixture was stirred at 90° C. for 14 hours. The reaction mixture was cooled down to room temperature, then water was added thereto and the mixture was extracted with ethyl acetate. The organic phase thus obtained was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to thus give the title compound (133 mg, yield: 90%). MS (ESI) m/z (M+H)+ 311
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl>C(O)(C)C.O1CCOCC1.C(Cl)Cl>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[C:7]3[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:18][CH:19]=1
Reactant: CN1CCN(C)c2c(N)cccc2C1=O
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC(C)O
Product: CN1CCN(C)c2c(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cccc2C1=O
Temperature: 130 °C
Yield: 22.1 %

Procedure:
9-Amino-1,4-dimethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (50 mg, 0.24 mmol) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methane sulfonamide (90 mg, 0.27 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (67 μL) was added, and the resulting mixture was heated to 130° C. in the microwave for 30 min. The resulting solution was diluted with CH2Cl2 (50 ml) washed with saturated aqueous NaHCO3 (2×50 ml), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes followed by 0-20% MeOH in EtOAc) to obtain N-{(1R,2R)-2-[5-Chloro-2-(1,4-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}methanesulfonamide as a beige foam (27 mg, 22%). LCMS: m/z=510.20 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.48 (m, 2H), 7.96 (s, 1H), 7.27 (m, 2H), 5.60 (m, 2H), 3.95 (m, 1H), 3.34 (m, 5H), 3.20 (s, 3H), 2.86 (s, 3H), 2.78 (s, 3H), 2.24 (m, 2H0, 1.83 (m, 2H), 1.39 (m, 4H).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][N:25]([CH3:34])[C:26](=[O:33])[CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30]>N1C=CC=CC=1.[Cu-]=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:28]([CH2:27][C:26]([N:25]([CH3:34])[CH3:24])=[O:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: CN(C)C(=O)CNS(C)(=O)=O
Agent: O=[Cu-]
Solvent: c1ccncc1
Product: CN(C)C(=O)CN(c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12)S(C)(=O)=O
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide (0.57 g, 1.5 mmol), N,N-dimethyl-2-[(methylsulfonyl)amino]acetamide from Step 1 (0.25 g, 1.38 mmol) and copper (I) oxide (0.10 g, 0.70 mmol) in pyridine (5 mL) was heated in an oil bath at 115° C. overnight. The resultant mixture was concentrated under vacuum. To the residue, chloroform (200 mL) and a saturated aqueous solution of ethylenediamine tetraacetic acid, disodium salt (75 mL) was added. The mixture was stirred vigorously at room temp for 2 hours in the presence of air, and filtered through a pad of Celite. The organic extract was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:26])[NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])([CH3:16])([CH3:15])[CH3:14].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.ClCCl>[C:13]([O:17][C:18](=[O:26])[NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][N:28]1[C:32](=[O:33])[C:31]2[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]1=[O:38])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(CNC(=O)OC(C)(C)C)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
Diethylazodicarboxylate (8.26 mL, 52.4 mmol) was added to a solution of (3-hydroxy-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (10.2 g, 49.9 mmol), N-hydroxyphthalimide (8.15 g, 49.9 mmol) and triphenylphosphine (13.1 g, 49.9 mmol) in THF (200 mL). The solution was stirred at room temperature for 16 hours after which time it was diluted with dichloromethane and passed through a plug of silica gel, eluting with dichloromethane. The product containing fractions were concentrated to a yellow liquid, which was further purified by flash column chromatography (dichloromethane to 4:1 dichloromethane/ethyl acetate) to provide pure desired product (1.98 g, 11%) as a waxy white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[N+](C1C=C(S(O[CH2:26][C@@H:27]2[O:29][CH2:28]2)(=O)=O)C=CC=1)([O-])=O>CN(C)C=O.C(OCC)(=O)C.CCCCCCC>[O:29]1[CH2:28][CH:27]1[CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cc(OCC2CO2)c2cc[nH]c2c1

Procedure:
4-hydroxy indole (0.08 g, mmol) was dissolved in dimethylformamide (1.5 mL). Sodium hydride (0.02 g, 0.51 mmol) was slowly added to the reaction mixture followed by addition of (R)-glycidyl 3-nitrobenzene sulfonate (0.132, 0.51 mmol). A red color appeared. After 3 hour the reaction mixture was poured into a separatory funnel and ethyl acetate (100 mL) was added. The organic layer was washed 3 times with a 10% solution of sodium carbonate in water. The aqueous layers were discarded, the organic layer was dried with sodium sulfate and the solvent was removed by reduced pressure to yield crude product. The crude product was dissolved in ethyl acetate, Celite® (approximately 3 grams) was added, followed by removal of the solvent under reduced pressure. The Celite®/reaction mixture was loaded into an Isco solid phase loading cartridge. Flash chromatography was carried out using an Isco Companion automated chromatography system, silica column (4 g), initially holding at 5% ethyl acetate in heptane for 3 column volumes, increasing the ethyl acetate concentration to 60% over 40 column volumes, holding at 60% ethyl acetate for 10 more column volumes to yield the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([C:10]([NH2:12])=[O:11])[NH:4][N:3]=1.[CH2:13]([OH:15])C.O>C(O)=O.[Pd]>[CH:13]([NH:7][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[C:10]([NH2:12])=[O:11])=[O:15]
Reactant: CCO
Reactant: Cc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: O
Product: Cc1n[nH]c(C(N)=O)c1NC=O
Reaction time: 8 h

Procedure:
A mixture of 3-methyl-4-nitropyrazole-5-carboxamide (17.0 g, 0.1 mol) in a mixture of 20 ml of 97-100% formic acid, 160 ml of ethanol and 30 ml of water was hydrogenated overnight at 40°-60° using 150 mg of 5% palladium-on-charcoal at 50 psi. Filtration of the hot solution through Celite and evaporation gave 17.8 g of crude, ochre-colored product which was recrystallized from ethanol: 1st crop 9.3 g colorless, 2nd crop 6.7 g brownish, total yield, 16.0 g (95%).