Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[S:6][C:7]=1[C:8](O)=[O:9]>O1CCCC1>[F:19][CH:2]([F:1])[C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[S:6][C:7]=1[CH2:8][OH:9]
Reactant: COc1ccc(-c2nc(C(F)F)c(C(=O)O)s2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C(F)F)c(CO)s2)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 104 %

Procedure:
2.73 g 4-Difluoromethyl-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid were dissolved in 30 ml tetrahydrofuran. 23 ml of a one molar solution of borane tetrahydrofuran complex were added and the reaction mixture stirred at 40° C. for three hours. The cooled reaction mixture was poured on ice water and extracted three times with portions of 100 ml ethyl acetate. The combined organic layers were dried over MgSO4. Then the solvent was removed in vacuo to obtain 2.70 g [4-difluoromethyl-2-(4-methoxy-phenyl)-thiazol-5-yl]-methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][NH:23][C@@H:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2].Cl[C:35]([O:37][CH3:38])=[O:36]>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][N:23]([C:35]([O:37][CH3:38])=[O:36])[C@@H:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc([N+](=O)[O-])cc2CN[C@@H](C)Cc2ccccc2)c1
Reactant: COC(=O)Cl
Product: CCOC(=O)Cc1cccc(Oc2ccc([N+](=O)[O-])cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: (3-{2-[((S)-1-methyl-2-phenyl-ethylamino)-methyl]-4-nitro-phenoxy}-phenyl)-acetic acid ethyl ester and methyl chloroformate.
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH2:24][CH3:25])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[C:3]([O:23][CH2:24][CH3:25])=[C:2]([C:34]4[CH:35]=[N:36][N:37]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:38]=4)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=3)[CH3:11])[N:13]=[C:14]([CH3:22])[C:15]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(CC(=O)OC(C)(C)C)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.16 mmol) (first peak from Example 195, step 4), tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate (65 mg, 0.21 mmol), sodium carbonate (30.0 mg, 0.28 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (23 mg, 0.028 mmol) in acetonitrile (3 mL)/water (0.7 mL) was degassed with N2 and then stirred at 95° C. for 2 h. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product (65 mg, 78%) was purified by chromatography eluting with CH2Cl2/MeOH (max. MeOH 5%). LCMS calculated for C26H33ClN7O3 (M+H)+: m/z=526.2; Found: 526.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[N:12]=1)[CH2:5][OH:6].C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([N:7]3[C@H:4]([C:3]([O:2][CH3:1])=[O:20])[CH2:5][O:6][C:29]3=[O:31])[S:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
2-[4-(4-Bromophenyl)-1,3-thiazol-2-ylamino]-3-hydroxy-propionic acid methyl ester (1.1 g, 3.08 mmol), prepared in the previous step, was dissolved in 40 mL of methylene chloride and triethylamine (4.3 mL, 30.8 mmol) was added. The mixture was cooled to 0° C. and triphosgene (2.3 g, 7.7 mmol) was added. The mixture was stirred for 1 h and then diluted with methylene chloride, washed with saturated NaHCO3, water, and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 2% acetone/hexane to 15% acetone/hexane) afforded the title compound (510 mg, 44%) as a white solid. mp 165-167° C. HRMS: calcd for C14H, BrN2O4S+H+, 382.96956; found (ESI, [M+H]+), 382.9718. Analytical HPLC: retention time 9.9 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:18])[CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:8][CH2:7]2.[Br:19]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:5]1[C:4](=[O:18])[NH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:10]2
Reactant: Cc1[nH]c(=O)cc2c1CC(c1ccncc1)CC2
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(Br)c2c1CC(c1ccncc1)CC2
Yield: 39.5 %

Procedure:
2,3,5,6,7,8-Hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline (0.4 g) obtained in Example 1 was dissolved in 6 ml of acetic acid, and a solution of 0.27 g of bromine and 1.3 ml of acetic acid was dropwise added at 45° C. After the reaction was completed, the reaction mixture was poured into water and an aqueous solution of sodium hydroxide was added to adjust the pH to 9-10. The deposit was filtered out and recrystallized from methanol. Thus, there was obtained 0.21 g of 4-bromo-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2.C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:27][C:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[F:1])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc(-c2ccc3cc(O)ccc3c2)c(F)c1
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)c(F)c1

Procedure:
The title compound was prepared by reacting 6-(2-fluoro-4-hydroxyphenyl)-2-naphthol (300 mg, 1.18 mmol) and NCS (191 mg, 1.43 mmol) in THF (30 mL) according to method C to yield 170 mg (50%) of yellowish solid: mp 179–180° C.; 1H NMR (DMSO-d6): δ 6.73 (1H, dd, J=12.69 Hz, J=2.44 Hz), 6.75 (1H, dd, J=8.30 Hz, J=2.44 Hz), 7.31 (1H, d, J=8.79 Hz), 7.45 (1H, t, J=9.28 Hz), 7.70–7.72 (1H, m), 7.83 (1H, d, J=8.79 Hz), 7.97 (1H, s), 8.06 (1H, d, J=7.79 Hz), 10.06 (1H, s), 10.48 (1H, s); MS (ESI) m/z 287/289 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](Cl)[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[Cl:18][C:19]1[CH:25]=[C:24]([I:26])[CH:23]=[C:22]([Cl:27])[C:20]=1[NH2:21]>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:21][C:20]3[C:19]([Cl:18])=[CH:25][C:24]([I:26])=[CH:23][C:22]=3[Cl:27])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Clc1nc2ccc(Br)cc2c2c(Cl)nccc12
Reactant: Nc1c(Cl)cc(I)cc1Cl
Product: Clc1cc(I)cc(Cl)c1Nc1nc2ccc(Br)cc2c2c(Cl)nccc12

Procedure:
The title compound was prepared according to the procedure in (Example 3, Method C, Step 4) using 9-bromo-1,5-dichlorobenzo[c]-2,6-naphthyridine and 2,6-dichloro-4-iodoaniline as the starting materials.
Reaction SMILES: [C:1]1([S:17]([O-:20])(=O)=[O:18])[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na+].O=P(Cl)(Cl)[Cl:24].S1(CCCC1)(=O)=O>C(#N)C>[Cl:24][S:17]([C:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:20])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)Cl
Temperature: 110 °C

Procedure:
Sodium anthraquinone-1-sulfonate (50.0 g) was combined with POCl3 (31 mL) and a 1:2 (v/v) mixture of sulfolane (100 mL) and acetonitrile (200 mL). The mixture was stirred and heated to 110° C. under a nitrogen atmosphere for 44 hours. The mixture was allowed to cool to room temperature and was then further cooled in a refrigerator. The mixture was filtered and the filtrate was poured onto ice in a beaker and this mixture was stirred for 1 hour. The brown precipitate was filtered, washed with deionized water, dried in air and then further dried overnight in a vacuum oven at 45° C. and less than 1 mmHg pressure to give 12.08 g of the product as a brown solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2].C(O)C>CO.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCC#N)c4c21)C(=O)NC3=O
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCCN)c4c21)C(=O)NC3=O
Reaction time: 20 h

Procedure:
760 mg (1.94 mmol) 12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole (Example 1a) in 100 ml methanol are hydrogenated in the presence of 500 mg Raney nickel at 60° C. and 50-65 bar pressure for 20 hours in an autoclave. The reaction mixture is evaporated, the residue is taken up in 100 ml dimethylformamide, filtered off from the catalyst and again evaporated in a vacuum. The residue is chromatographed on silica gel with dichloromethane/methanol saturated with ammonia (95:5 v/v). The fraction with the Rf of 0.1 is isolated, stirred with ethanol and the undissolved product is filtered off. 12-(3-aminopropyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole is obtained as an amorphous yellow powder which decomposes from about 250° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([N+:40]([O-])=O)[CH:39]=1)[C:7]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)=[O:8])([O-])=O>CN(C)C=O.O.[Zn]>[NH2:40][C:38]1[CH:37]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:39]=1)[C:7]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)=[O:8]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5cc([N+](=O)[O-])cc([N+](=O)[O-])c5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5cc(N)cc(N)c5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 80.1 %

Procedure:
11.42 g (19.66 mmol) of (3-β)-cholest-5-en-3-yl 3,5-dinitrobenzoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 32.6 g (120 mmol) ferric chloride hexahydrate are added. 13.1 g (201 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yielded 8.20 g of (3-β)-cholest-5-en-3-yl 3,5-diaminobenzoate as yellowish crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH2:20]Br)[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8].[F-].[K+].[F:25][B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC>C(#N)C.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH2:20][F:25])[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1O[C@@H](Cn2cc(CBr)nn2)CN1c1ccc(I)c(F)c1
Reactant: F[B-](F)(F)F
Agent: CCCC[n+]1ccn(C)c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1O[C@@H](Cn2cc(CF)nn2)CN1c1ccc(I)c(F)c1
Temperature: 90 °C
Yield: 45 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-[(4-bromomethyl-1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (Intermediate 17, 6.94 g, 14.4 mmol) was dissolved/suspended in acetonitrile (250 mL) and water (1.5 mL). Potassium fluoride (4.19 g, 72.1 mmol) was added, followed by addition of 1-butyl-3-methylimidazolium tetrafluoroborate (18.4 mL) and the solution was heated to 90° C. over night. It was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. Chromatography on silica gel with ethyl acetate gave 2.7 g (45%) of the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([CH3:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]3[O:41][CH:40]=[CH:39][C:38]=3[CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[O:41]1[C:37]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][C@@H:14]5[CH2:18][CH2:17][N:16]([C:19]([CH:21]6[CH2:23][CH2:22]6)=[O:20])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:24])=[C:4]([CH3:25])[CH:3]=3)=[CH:42][C:38]=2[CH:39]=[CH:40]1
Reactant: Cc1cc(Br)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3occc3c2)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Temperature: 150 °C
Yield: 36.4 %

Procedure:
A microwaveable vial was charged with 4-(4-bromo-2-methylphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.247 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (63.2 mg, 0.259 mmol), PdCl2(dppf) (9.03 mg, 0.012 mmol), K2CO3 (85 mg, 0.617 mmol), 1,4-dioxane (3 mL) and water (1 mL). The reaction was purged with nitrogen, sealed and heated in a microwave reactor at 150° C. for 30 min (LCMS indicated complete conversion of starting material to desired product). The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO, filtered through a syringe filter and purified by reverse phase HPLC (Gilson, YMC-Pack ODS-A C18 5 μm 75×30 mm column, 10-90% MeCN/water+0.1% TFA, 3×1 mL injections). The appropriate fractions were concentrated to dryness and the residue was diluted with water (10 mL) and adjusted to pH 5 with conc. NH4OH. The resulting precipitate was collected by filtration and dried to constant weight under vacuum to provide the title product (40 mg, 0.090 mmol, 36.6% yield) as a white solid. MS(ES)+ m/e 443.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=O.[Cl:13][C:14]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N=C=NC(C)C)(C)C>ClC(Cl)C>[Cl:13][C:14]1[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:9](=[O:11])[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:12]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CC(C(=O)O)c1ccccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC(Cl)Cl
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Reaction time: 16 h
Yield: 37 %

Procedure:
A solution of 2-(2-chlorophenyl)propionic acid (350 mg, 1.9 mmole) and 2-chloro-3-trifluoromethylbenzylamine (398 mg, 1.9 mmole) in 5 mL of dichloroethane was treated with diisopropylcarbodiimide (0.3 mL, 1.9 mmole) and the reaction was stirred for 16 hours. The solvent was removed, and the residue taken up in Et2O. The Et2O was washed with H2O, 0.1N HCl, and aqueous Na2CO3, dried and the solvent removed. Recrystallization from a mixture of CH2Cl2 and hexane gave the titled compound, 265 mg (37% yield). MS (ESI) 376 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>ClCCl.CC(C)=O>[CH2:26]([O:25][C:23](=[O:24])[C:22](=[CH:21][NH:1][C:2]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(OCc2ccccc2)c(=O)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)C(=CNc1ccc(OCc2ccccc2)c(=O)cc1)C(=O)OCC
Temperature: 140 °C

Procedure:
A mixture of 5-amino-2-benzyloxy-2,4,6-cycloheptatrien-1-one (10 g), described in example 1b, and diethyl ethoxymethylenemalonate (100 ml) was heated at 140° C. for 1.5 hr. The cooled reaction mixture was subjected to chromatography on silica gel using dichloromethane-acetone (9:1) as the eluant. The pure fractions were pooled to give 2-[(4-benzyloxy-5-oxo-1,3,6-cycloheptatrien-1-yl)aminomethylene]propanedioic acid diethyl ester (V; R7 =OCH2C6H5 and R8 =C2H5); nmr (CDCl3) δ1.3 (m 6H), 4.2 (m, 4H), 5.2 (s, 2H), 7.2 (m, 2H), 7.2 (m, 9H), 8.25 (d, 1H), 10.9 (d, 1H); ir (CHCl3) 3490, 3240, 1700, 1690, 1570; uv λmax (MeOH) 279 nm (ε10,410), 224 (27,380).
Reaction SMILES: [CH2:1]([C:3]([CH:10]([CH3:28])[C:11](=[O:27])[C:12]1[CH:26]=[CH:25][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][C:14]=2[CH:13]=1)(C(O)=O)[C:4]([OH:6])=[O:5])[CH3:2].C(O)COCCO.COC>O>[CH2:1]([CH:3]([CH:10]([CH3:28])[C:11](=[O:27])[C:12]1[CH:26]=[CH:25][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:18][C:14]=2[CH:13]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(C(=O)O)(C(=O)O)C(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: COC
Solvent: OCCOCCO
Solvent: O
Product: CCC(C(=O)O)C(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
200 mg (524 μmol) 2-ethyl-2-[1-methyl-2-oxo-2-(2-phenyl-benzoxazol-6-yl)-ethyl]-malonic acid are heated together with 5 ml diethyleneglycol-dimethylether for 1 h at 140° C. in the microwave. The solv. is largely removed i.V., the residue is mixed with a little water and freeze-dried.
Reaction SMILES: [N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[N:19]=[C:18]4[NH:20][C:21]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])=[N:22][C:17]4=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:31]=[N+:32]=[N-:33].[Na+].II>CN(C)C=O>[N:27]1[NH:31][N:32]=[N:33][C:26]=1[C:25]1[CH:24]=[C:23]([C:21]2[NH:20][C:18]3=[N:19][C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[O:7])[CH2:9]4)=[CH:15][CH:16]=[C:17]3[N:22]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: N#Cc1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Reactant: [N-]=[N+]=[N-]
Agent: II
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(-c5nn[nH]n5)c4)[nH]c3n2)C1)N1CCCC1
Temperature: 120 °C
Yield: 116 %

Procedure:
To a solution of (R)-3-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzonitrile (30 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) were added sodium azide (6 mg, 0.09 mmol) and iodine (3 mg). The reaction mixture was heated for 12 h at 120° C., then was cooled. The mixture was filtered, and the filtrate was concentrated. The resulting residue was triturated with diethyl ether to afford (R)-(1-(2-(3-(2H-tetrazol-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone as yellow solid (36 mg, 92%). MS (ES+APCI) (M+H) 444.1; HPLC retention time 3.551 min (Method C1). 1H NMR (400 MHz, DMSO-d6) δ 1.50-2.00 (m, 8H), 2.60-2.68 (m, 1H), 2.83-2.97 (m, 3H), 3.25-3.31 (m, 1H), 3.42-3.50 (m, 1H), 3.52-3.60 (m, 1H), 4.32 (d, 1H), 4.42 (d, 1H), 6.83 (d, 1H), 7.47 (t, 1H), 7.81 (d, 1H), 7.94-8.02 (m, 2H), 8.79 (s, 1H), 13.02 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[N-]=C=O.ClC1C=CC=CC=1C(O[CH:37]1[CH2:40][N:39]([C:41](NC(C)(C)C)=[O:42])[CH2:38]1)C1C=CC=CC=1Cl>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([O:13][CH:14]1[CH2:17][N:16]([C:41]([NH:39][CH2:38][CH2:37][CH3:40])=[O:42])[CH2:15]1)[C:4]1[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=1[Cl:2]
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Agent: Cl
Agent: [N-]=C=O
Product: CCCNC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](SC)[N:3]=1.OO.CSC.C(N(CC)CC)C.[CH3:32][CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>C(O)(C(F)(F)F)=O.CCOCC.CCCCCC.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:34]2[CH2:35][CH2:36][CH2:37][CH:33]2[CH3:32])[N:3]=1
Reactant: CSc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: CC1CCCN1
Agent: OO
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1CCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.250 g, 0.918 mmol) in TFA (8.7 mL) at 0° C. was added aqueous H2O2 (0.375 mL, 3.67 mmol, 30% (w/w)) dropwise over 3 minutes. Upon completion of addition, the reaction was allowed to warm to room temperature. After 2 hours, LCMS showed complete conversion to the sulfone. The reaction was cooled to 0° C. and quenched with dimethyl sulfide (0.54 mL, 7.34 mmol). The reaction was allowed to warm to room temperature and stirred for 10 minutes. The mixture was cooled to 0° C. and diluted with Et2O (10 mL) and hexane (5 mL). The resulting orange precipitate was filtered, washed with hexane and placed into a 25 mL sealable tube. 1,4-Dioxane (5.83 mL) and triethylamine (0.51 mL, 3.67 mmol) were added followed by 2-methylpyrrolidine (0.12 mL, 1.19 mmol). The tube was sealed, and the reaction mixture was stirred overnight at 95° C. LCMS analysis of the reaction mixture showed 60% desired product and 30% unreacted sulfone. More 2-methylpyrrolidine (0.1 mL) was added and the reaction mixture was stirred for 2 additional hours at 95° C. The reaction was cooled to room temperature and decanted. The solution was concentrated, and the resulting residue was dissolved in 3 mL of 50/50 CH3CN/H2O w/0.1% TFA. Purification on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA) afforded a TFA salt of the title compound (105 mg, 20%) as a yellow solid as a mixture of rotamers. LC-MS (ES) m/z=310 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.22-1.26 (m, 3H), 1.65-1.87 (m, 1H), 1.93-2.16 (m, 3H), 3.47-3.64 (m, 1H), 3.65-3.87 (m, 1H), 4.31-4.54 (m, 1H), [6.54 (s) and 6.63 (s)] (1H), 7.36 (d, J=8.6 Hz, 1H), 7.72 (s, 1H), 7.91 (m, 1H), 11.99 (bs, 2H).