Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:35])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39](=[O:59])[CH2:40][C:41]1([C:44]2[CH:49]=[CH:48][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:45]=2)[CH2:43][CH2:42]1)[CH3:37]>>[CH2:36]([O:38][C:39](=[O:59])[CH2:40][C:41]1([C:44]2[CH:49]=[CH:48][C:47]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:35])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=5)=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42]1)[CH3:37]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)Cc4ccc(OCc5ccc(C(F)(F)F)cc5)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-{1-methyl-2-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-ethyl}-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:39](NC1N=C(C2C=CC=C(C)N=2)C=C(C2C=NC=C(Br)C=2)C=1)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:39])[N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2cc(-c3cncc(Br)c3)cc(NCc3ccccc3)n2)n1
Reactant: CC(C)N1CCN(CC#Cc2cncc(-c3cc(NCc4ccccc4)nc(-c4ccccn4)c3)c2)CC1
Product: Cc1cccc(-c2cc(-c3cncc(C#CCN4CCN(C(C)C)CC4)c3)cc(NCc3ccccc3)n2)n1

Procedure:
This compound is prepared analogously to Benzyl-{5″-[3-(4-isopropyl-piperazin-1-yl)-prop-1-ynyl]-[2,2′;4′,3″]terpyridin-6′-yl}-amine (Example 2.139) by replacing Benzyl-(5″-bromo-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 1.25) with Benzyl-(5″-bromo-6-methyl-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 2.40, step1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH:20]1[CH2:23][CH2:22][CH2:21]1>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:19][CH:20]2[CH2:23][CH2:22][CH2:21]2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CCC1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1cc(OCc2ccccc2)ccn1CC1CCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.1 %

Procedure:
A solution of 4-benzyloxy-1H-pyridin-2-one (0.60 g, 2.98 mmol) in N,N-dimethylacetamide (10 mL) at 0° C. was treated with sodium hydride (0.086 g, 3.58 mmol) for 30 min, then bromomethyl cyclobutane (0.40 mL, 3.58 mmol) was added and the mixture was stirred at 25° C. for 48 hours. The solution was partitioned between 10% aqueous ammonium chloride solution and dichloromethane, the organic layer was separated, concentrated under reduced pressure and the residue was chromatographed on silica gel, eluting with 1% methanol in dichloromethane to provide the title compound (0.426 g, 53%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@@H:19]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:18][C@@H:13]2OC(=O)C)[CH3:10])[C:4](=[O:35])[CH2:3]1.[BrH:37]>C(O)(=O)C.C(Cl)Cl>[CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@@H:19]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:18][C@@H:13]2[Br:37])[CH3:10])[C:4](=[O:35])[CH2:3]1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-1,3,4,6-tetra-O-acetyl-α-D-glucopyranose (100 mg, 0.19 mmol) and HBr in acetic acid (45%) (1.0 ml) was stirred at room temperature for 30 min. The reaction mixture was diluted with cold CH2Cl2 (10 ml), washed twice with cold H2O (30 ml), saturated NaHCO3 solution (20 ml) and with H2O again (20 ml). The organic phase was dried over MgSO4 and evaporated, giving 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranosyl bromide (3) (95 mg, 91%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:27]([N+:35]([O-:37])=[O:36])=[CH:26][CH:25]=1.[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[C:46]1[C:51]([C:52]2[NH:53][CH:54]=[CH:55][N:56]=2)=[CH:50][N:49]=[C:48]([NH:57][CH2:58][CH2:59][NH:60]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:47]=1>>[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[C:46]1[C:51]([C:52]2[NH:56][CH:55]=[CH:54][N:53]=2)=[CH:50][N:49]=[C:48]([NH:57][CH2:58][CH2:59][NH:60][C:24]2[N:29]=[C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:27]([N+:35]([O-:37])=[O:36])=[CH:26][CH:25]=2)[N:47]=1
Reactant: CS(=O)(=O)Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CS(=O)(=O)Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]-3-nitro(2-pyridyl)}(methylsulfonyl)amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and (6-chloro-3-nitro(2-pyridyl))(methylsulfonyl)amine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([CH3:49])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([CH3:49])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(Cc4ccccc4)CC3)CC2)cc(C)c1O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc(C)c1O
Temperature: 25 °C

Procedure:
A solution of 54 mg (0.08 mmol) of (R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 78) in 5 mL MeOH were combined with 20 mg of 10% Pd/C and shaken at RT and 3 bar hydrogen until the reaction stopped. The catalyst was suction filtered and the solvent evaporated down i.vac. The residue was triturated with DIPE, suction filtered and dried under a high vacuum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.CCN(CC)CC.Cl>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CCOCC>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(SCC#Cc2ccc(C(F)(F)F)cc2)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A degassed (argon) solution of 96.0 mg (0.33 mmol) (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester, 0.053 ml (0.36 mmol) 1-iodo-4-trifluoromethyl-benzene and 0.086 (0.621 mmol) Et3N in 1 ml DMF was treated with 37.9 mg (0.03 mmol) Pd(PPh3)4 and 12.5 mg (0.07 mmol) of CuI. After stirring for 2 h at room temperature, the reaction was distributed between 1N HCl and ether (three times). Washing of the organic layer with saturated aqueous NH4Cl solution and brine, drying (Na2SO4) and evaporation of the solvents, followed by flash chromatography (SiO2, n-heptane/EtOAc 1 to 5%), yielded 76 mg of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([OH:26])[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:27](Cl)Cl>O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][CH3:27])[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCCCOC(=O)c1nc(O)c2ccccc2c1OCc1ccccc1
Solvent: O
Product: CCCCOC(=O)c1nc(OC)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
A mixture of 4-benzyloxy-1-hydroxy-isoquinoline-3-carboxylic acid butyl ester (1 eq.), Me3OBF4 (6 eq), KHCO3 (14 eq) and CH2Cl2 (10 ml/mmol 4-benzyloxy-1-hydroxy-isoquinoline-3-carboxylic acid butyl ester) was stirred at ambient temperature for 24 h. Then water (10 ml/mmol) was added and the mixture was extracted with CH2Cl2 (40 ml/mmol). The organic phase was separated, dried over MgSO4 and evaporated in vacuo to give a yellowish solid. The crude product was purified by flash column chromatography on silica gel using hexanes:EtOAc=85:15 as the eluent. Evaporation of the first fraction gave the title compound as a colorless oil in 20% yield; 1H NMR (CDCl3): δ=8.21 to 8.25 (m, 1 H), 8.05 to 8.09 (m, 1 H), 7.33 to 7.73 (m, 7 H), 5.13 (s, 2 H), 4.38 (t, 2 H), 4.16 (s, 3 H), 1.69 (m, 2 H), 1.37 (m, 2 H), 0.94 (t, 3 H).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([CH3:24])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:5].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>>[CH3:5][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])([CH3:24])[C:3]([OH:2])=[O:25]
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CNC(=O)N2C)cc1C
Reactant: BrCc1ccc2ccccc2c1
Product: Cc1cc(CCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2C)ccc1OC(C)(C)C(=O)O

Procedure:
The titled compound was prepared using 2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid methyl Ester (0.100 g, 0.287 mmole) and 2-Bromomethyl-naphthalene (0.095 g, 0.431 mmole) to produce an oil (0.080 g, 59%). Mass [EI+] 476 (M+H)+, [EI−] 474 (M−H)−.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH:10]([O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd]>[C:16]([O:15][CH:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:24])=[O:8])(=[O:23])[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: CC(C)CC(OC(=O)c1ccncc1)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CC(C)CC(OC(=O)c1ccncc1)C(=O)O

Procedure:
8.2 g of benzyl-(RS)-2-(isonicotinoyloxy)-isocaproate were hydrogenated in 50 ml of alcohol after the addition of 800 mg. of palladium-on-charcoal (5%) until the theoretical amount of hydrogen had been taken up. The catalyst was then filtered off and the filtrate evaporated under reduced pressure at 45°. The resulting oil was dissolved in excess sodium bicarbonate solution and extracted twice with 20 ml portions of ether and the bicarbonate solution adjusted to pH 2.5 with 3-N hydrochloric acid. The acidic solution was extracted twice with 70 ml portions of ethyl acetate. After being washed twice with 20 ml portions of 5% sodium chloride solution, the ethyl acetate solution was dried with magnesium sulphate and evaporated under reduced pressure at 45°. The resulting oil was crystallized from ether/petroleum ether to yield (RS)-2-(isonicotinoyloxy)-isocaproic acid; mp 98°-100°.
Reaction SMILES: [H-].[Na+].[H][H].[Cl:5][C:6](Cl)=[CH:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].Cl>CO.CN(C)C=O>[Cl:5][C:6]#[C:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: OCCCCOCC=C(Cl)Cl
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OCCCCOCC#CCl
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
In a reaction vessel containing 10 ml of N,N-dimethylformamide and 0.088 g of 60% sodium hydride (in oil) was put 0.070 g of methanol under ice cooling, and the mixture was stirred until the evolution of hydrogen gas ceased, to which 0.40 g of 4-(3,3-dichloro-2-propenyloxy)butanol was added. After stirring at 50° C. for 3 hours, the reaction mixture was poured into diluted hydrochloric acid and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.20 g of 4-(3-chloro-2-propynyloxy)butanol (yield, 62%), nD24.6 1.4720.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:2]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CN(C)CC(O)=O>O1CCOCC1.CCOC(C)=O.O>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([O:13][C:10]2[CH:11]=[CH:12][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=2)=[CH:32][CH:33]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Oc1ccc(-c2cccnc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Agent: CN(C)CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cccnc3)cc2)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 48.2 %

Procedure:
To a solution of product from step 2 (114 mg, 0.66 mmol) in dioxane (2 mL) was added (R)-2-(4-iodo-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (403 mg, 1.0 mmol) in dioxane (1.5 mL) and cesium carbonate (432 mg, 1.33 mmol). The vessel was purged with nitrogen for 15 min before N,N-dimethylglycine hydrochloride (9 mg, 0.06 mmol) in dioxane (0.5 mL) and Cu(I) iodide (4 mg, 0.02 mmol) were added. The resulted mixture was stirred at 90° C. for 48 h. It was then diluted with EtOAc and water, organic layer was separated, washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo to yellow oil. The crude mixture was purified by silica gel flash chromatography (15% EtOAc/Hexane) to obtain the title product as yellow oil (142 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[C@H:31]1([NH2:38])[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[NH2:37].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:37][C@H:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]4[NH2:38])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC[C@@H]4N)n3)c3cc(Cl)cnc32)cc1

Procedure:
A solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 23a, (0.50 g, 1.08 mmol) in THF (4 mL) was treated with (1S,2S)-cyclohexane-1,2-diamine (0.27 g, 2.37 mmol) and iPr2NEt (2.15 mmol) at 120° C. for 10 minutes. The mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH—CH2Cl2) to provide the desired intermediate as a white solid (410 mg).
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=O)=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[CH3:23][NH:24][CH3:25]>O>[CH3:23][N:24]([CH2:18][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[C:10]3[C:14]4=[C:6]([CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]4[CH:12]=[CH:11]3)[CH:7]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:25]
Reactant: O=Cc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Reactant: CNC
Solvent: O
Product: CN(C)Cc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Yield: 87 %

Procedure:
Using the reductive amination procedure described in Example 82, the title compound was synthesized from 3-(1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-6-yl)-benzaldehyde and dimethylamine in 87% yield as a white solid: mp 98-100° C.; 1H NMR (DMSO-d6) δ 2.18 (s, 6H), 3.47 (br s, 4H), 4.30-4.32 (m, 2H), 6.70 (s, 1H), 7.17 (t, 1H, J=6.0 Hz), 7.35-7.37 (m, 1H), 7.43-7.50 (m, 3H), 7.78 (d, 1H, J=6.0 Hz), 7.81 (d, 1H, J=6.0 Hz), 8.38 (t, 1H, J=6.0 Hz). HRMS calcd. for C20H21N3O 319.1685 (M+), found 319.1682. Anal. (C20H21N3O.0.25 H2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2Br)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[C:3]=1[C:30]([NH2:32])=[O:31].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[N+:13]([C:11]1[CH:10]=[CH:9][C:8]2[NH:1][C:2]3[N:6]([N:5]=[C:4]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:19][CH:18]=4)[C:3]=3[C:30]([NH2:32])=[O:31])[C:7]=2[CH:12]=1)([O-:15])=[O:14]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2Br)c1N
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c1ccc([N+](=O)[O-])cc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
A mixture of 5-amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (149 mg, 0.3 mmol, crude), CuI (5.7 mg, 0.03 mmol), N1,N2-dimethylethane-1,2-diamine (3 mg, 0.03 mmol), K3PO4 (64 mg, 0.3 mol) in 15 mL of DMF was stirred at 60° C. under N2 for 5 hr, until TLC analysis showed that most of starting material was consumed. The reaction was cooled to RT. The solvent was removed under reduced pressure. The residue was chromatographed on 5 g of silica gel using DCM/MeOH (200/1 to 20/1) to afford 62 mg (52%) of 7-nitro-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide as a tan solid. MS (ESI) m/e [M+1]+ 414.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)[CH2:9]2)[O:7][NH:30]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorophenyl)piperidine-1-carboxylate (810 mg, 2.09 mmol) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.615 mL, 2.09 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.128 mL, 2.09 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (10.77 mL, 64.62 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluoro-phenyl)piperidine-1-carboxylate (355 mg, 48%) was isolated. MS m/z 357 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])[CH2:14][NH:13][C:12]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])[CH2:14][N:13]([S:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:50])=[O:49])[C:12]1=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CNC(=O)N3C(=O)OCc3ccccc3)CC2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-2-oxo-imidazolidine-1-carboxylic acid benzyl ester (1.0 g), N-ethyl-diisopropylamine (0.43 mL) and 4-dimethylaminopyridine (0.14 g) in dichloromethane (15 mL) was added benzenesulfonyl chloride (0.35 mL) at 0° C. The mixture was stirred at ambient temperature for 3 h, a diluted aqueous solution of NaHCO3 was added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (SiO2, dichloromethane/methanol 98:2) to yield (S)-3-benzenesulfonyl-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-2-oxo-imidazolidine-1-carboxylic acid benzyl ester (1.08 g) as a white solid. MS: 576.8, ([M+H]+)