Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[N:16](C3CCCCO3)[N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].Cl.O.[OH-].[Na+]>CCO>[N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
To a solution of 2-nitro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile (17.7 g, 59 mmol) in EtOH (440 ml) was added 44 ml of concentrated HCl. The reaction mixture was stirred at RT for 1.5 h. The mixture was poured into water (1 l), and 2 M NaOH-solution was added until pH was 12. Thus resulting precipitate was filtered, washed with water and dried to give 11.7 g (92%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 7.09 (d, 1H), 7.91 (d, 1H), 8.20 (d, 1H), 8.37 (dd, 1H), 8.73 (d, 1H), 13.4 (bs, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[O:8])[CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[C:10]1=[O:18])(=[O:21])[CH3:20]
Reactant: O=C1Nc2ccccc2C1C(=O)c1cccnc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)C(C(=O)c2cccnc2)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 476 mg (2.0 mmole) of 3-(3-pyridylcarbonyl)-2-oxindole and 4 ml of acetic anhydride was heated under reflux for 30 minutes The reaction mixture was cooled to room temperature, the bulk of the acetic anhydride was removed by evaporation in vacuo and the residue was triturated under 15 ml of water. The solid was recovered by filtration, dried and triturated under isopropanol. The residue (158 mg) was recrystallized from acetonitrile giving 64 mg of the title compound as red-orange crystals, m.p. 142.5°-143.5° C. A second crop of title compound (40 mg) was obtained from the mother liquors from the recrystallization. The two crops were the same by thin-layer chromatography. The first crop was subjected to elemental analysis.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1B1OC(C)(C)C(C)(C)O1)[C:17]([O:19]C)=[O:18]>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:23]1[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[CH3:13])[CH:11]=[CH:10]2
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: Cc1cc(C(=O)O)ccc1-c1ccc2cc(O)ccc2n1

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol and methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. 1H NMR (DMSO-d6, 400 MHz): δ 10.45 (brs, 1H), 8.61-8.46 (m, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 2.42 (s, 3H). MS (ESI): m/z 279.9 [M+H]+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][C:33]([F:32])([F:44])[F:45])[CH:36]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(OC(F)(F)F)c1)N1CCN(C2CCC2)CC1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-(trifluoromethoxy)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (61%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:16])[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]3[CH2:36][CH2:37][C:38](=[O:39])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].C1(C)C=C(C)C=C(C)C=1S(O[NH2:52])(=O)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][S:21](=[NH:52])(=[O:24])[CH2:20][CH2:19]3)=[O:16])[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)[C:11]3[CH2:36][CH2:37][C:38](=[O:39])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=O)CC2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=N)(=O)CC2)cc1
Temperature: 25 °C

Procedure:
4-(4-Cyanophenyl)-2,5-dioxo-N-(1-oxo-hexahydro-1λ4-thiopyran-4-yl)-1-(3-(trifluoro-methyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxamide (example 43, 40 mg, 72 μmol) is added to a solution of O-mesitylenesulfonylhydroxyl-amine (66 mg, 0.31 mmol) in dichloromethane (1.0 mL), and the mixture is stirred at room temperature over night. All volatiles are removed under reduced pressure, and the residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 9 mg; ESI mass spectrum [M+H]+=572; Retention time HPLC: 0.90 min (Z018_S04).
Reaction SMILES: [N:1]1([CH2:6][C:7](=[O:16])[C:8]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CS(C)=O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:7](=[O:16])[C:8]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)([CH3:10])[CH3:9])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C(=O)Cn1ccnc1)C1OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C(=O)C(Cc1ccc(Cl)cc1)n1ccnc1)C1OCCO1
Reaction time: 15 h
Yield: 30.6 %

Procedure:
30 g (0.131 mol) of 1-(imidazol-1-yl)-3-(dioxolan-2-yl)-3-methyl-butan-2-one are dissolved in 130 ml of dimethylsulphoxide, 7.5 g of powdered potassium hydroxide are added at 10° C., and 21 g of 4-chlorobenzyl chloride (0.131 mol), dissolved in 30 ml of dimethylsulphoxide, are added dropwise. After stirring has been carried out for 15 hours at 20° C., the suspension is poured onto 500 ml of water, the mixture is extracted with 600 ml of methylene chloride, the organic phase is extracted with 1 liter of water in each case, and the solvent is distilled off. The oily residue is taken up in 300 ml of diethyl ether, the other phase is filtered and the solvent is distilled off. 14 g (30.6% of theory) of 1-(4-chlorophenyl)-4-(dioxolan-2-yl)-2-(imidazol-1-yl)-4-methyl-pentan-3-one of refractive index nD20 =1.5490 are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](Br)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1B(O)O.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26]([C:35]6[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:34]=6[CH3:33])=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21
Reactant: Cc1cccc(C)c1B(O)O
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5-c5c(C)cccc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-(2-bromo-pyridin-3-yl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-dimethyl-phenylboronic acid following a procedure analogous to that described in Step 5 of Intermediate 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2.Cl[C:33]1[N:38]=[C:37]([C:39]#[N:40])[CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:33]2[N:38]=[C:37]([C:39]#[N:40])[CH:36]=[CH:35][CH:34]=2)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2
Reactant: N#Cc1cccc(Cl)n1
Reactant: COc1ccc(B(O)O)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
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: COCCOC
Solvent: O
Product: COc1ccc(-c2cccc(C#N)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
A suspension of the [4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]boronic acid produced in Example 1-1 (1.01 g, 2.37 mmol), 6-chloropyridine-2-carbonitrile (342 mg, 2.37 mmol), sodium carbonate (1.01 g, 9.48 mmol), and tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.12 mmol) in 1,2-dimethoxyethane (20.1 ml) and water (8.7 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 90° C. for 45 minutes. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=1:1, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (1.09 g, yield: 95%).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:9]2=[NH:28])[N:6]=1.[C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.[Cu]I>[C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:36]1[CH2:37][CH2:38][N:39]([C:2]2[S:3][CH:4]=[C:5]([CH2:7][N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]([CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:9]3=[NH:28])[N:6]=2)[CH2:40][CH2:41]1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1csc(Cl)n1
Reactant: c1ccc(-c2ccccc2CN2CCNCC2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1csc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)n1
Temperature: 190 °C
Yield: 7.9 %

Procedure:
To a solution of 1-(2-chloro-thiazol-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (30 mg, 0.072 mmol) in N-methylpyrrolidinone (2 ml) was added 1-biphenyl-2-ylmethyl-piperazine (18 mg, 0.072 mmol), CuI (14 mg, 0.072 mmol) and K2CO3 (15 mg, 0.11 mmol). The reaction was heated in a microwave at 190° C. for a total of 1.5 h. After this time, the suspension was cooled to rt and filtered through Celite®. The collected solids were washed with dichloromethane and then the combined filtrate and washings were washed with H2O. The aqueous phase was extracted with additional dichloromethane and the combined organic fractions were then washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC. The product was free-based by partitioning between a saturated solution of NaHCO3 and dichloromethane. The organic layer was then separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-[2-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-thiazol-4-ylmethyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (3.6 mg, 8%). HPLC-MS 633 [M+1]+, 317 (100%).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[Zn](CC)CC.C(I)I.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH:25]1[N:29]2[CH:30]=[N:31][CH:32]=[C:28]2[C:27](=[CH2:33])[CH2:26]1)[C:20]#[N:21]>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20]#[N:21])[CH:22]=[CH:23][C:24]=1[CH:25]1[N:29]2[CH:30]=[N:31][CH:32]=[C:28]2[C:27]2([CH2:1][CH2:33]2)[CH2:26]1
Reactant: C=C1CC(c2ccc(C#N)cc2F)n2cncc21
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: N#Cc1ccc(C2CC3(CC3)c3cncn32)c(F)c1
Reaction time: 2 h

Procedure:
A solution of TFA (0.234 mL, 3 mmol) in 0.6 mL of dry CH2Cl2 is added dropwise to a solution of Et2Zn (1M in Hexanes, 3.06 mL, 3.06 mmol) at 0° C. The resulting suspension is subsequently treated with a solution of CH2I2 (0.246 mL, 3.06 mmol) in CH2Cl2 (0.4 mL). After 2 h at 0° C., a solution of 3-fluoro-4-(7-methylene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (333.8 mg, 1.392 mmol) in CH2Cl2 is added. After overnight, the reaction is quenched with saturated NaHCO3 solution, and extracted with CH2Cl2 (20 mL×4). The combined extracts are washed with brine, dried over anhydrous Na2SO4. After filtration and evaporation, the residue is purified by chromatography and yield 112 mg of oil. MS (ESI) m/z 254.2 (M+H). 1H NMR (400.3 MHz, CDCl3): δ 8.93 (s, 1H), 7.54-7.52 (m, 1H), 7.45 (d, J=8.00 Hz, 1H), 7.35 (m, 1H), 6.83 (s, 1H), 6.27 (brs, 1H), 3.22 (m, 1H), 2.61 (d, J=12 Hz, 1H), 1.33-1.19 (m, 2H), 1.16-1.14 (m, 1H), 0.90-0.85 (m, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:23](O)=[O:24])([CH3:19])([CH3:18])[CH3:17].C(NC1CCCCC1)(NC1CCCCC1)=O.ON1C2C=CC=CC=2N=N1.[CH3:60][CH:61]1[NH:65][CH2:64][C:63]2([CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]2)[S:62]1>ClCCl.O>[C:30]([C:27]1[CH:26]=[C:22]([C:23]([N:65]2[CH2:64][C:63]3([CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]3)[S:62][CH:61]2[CH3:60])=[O:24])[CH:21]=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[C:28]=1[OH:29])([CH3:31])([CH3:33])[CH3:32]
Reactant: CC1NCC2(CCN(C)CC2)S1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC1SC2(CCN(C)CC2)CN1C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of dicyclohexylcarbodiimide (985 mg, 4.77 mmol) in dry and distilled dichloromethane (10 ml) was added to a stirred solution of 3,5-di-tert-butyl-4-hydroxybenzoic acid (1.14 g, 4.55 mmol) in dichloromethane (15 ml) at room temperature under an argon atmosphere. Dicyclohexylurea began to precipitate as a white solid. 1-Hydroxybenzotriazole (645 mg, 4.77 mmol) was added and the resulting solution was stirred at room temperature for 5 min. 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (846 mg, 4.55 mmol) in dichloromethane (5 ml) was then added and the resulting mixture was kept at room temperature overnight. The next day mixture was heated at 30° C. (temperature of water bath) for 5 hrs and then kept at room temperature for another 4 days. The resulting suspension was filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 140/10/1) to give two fractions: AF723 (224 mg, 99.16% chemical purity) and a mixture of AF723 with a by-product (943 mg). The mixture of AF723 with by-product was purified by flash chromatography in a COMBI-flash system using linear gradient (silica, CH2Cl2/EtOH/NH4OH 220/10/1 to 140/10/1). After evaporation and drying under vacuum, AF723 (516 mg, 100% chemical purity) was obtained as a white solid. 1H NMR. (CDCl3, 500 MHz) δ 7.27 (s, 2H, arom CH), 5.55 (m, 1H, CH—S), 5.44 (s, 1H, OH), 4.10 (m, 1H, CHH—N—CO), 3.40 (m, 1H, CHH—N—CO), 2.60 (m, 2H, CH2—NCH3), 2.28 (m, 1H, CHH—NCH3), 2.25 (s, 3H, NCH3), 2.11 (m, 1H, CHH—NCH3), 1.95-1.66 (m, 4H, two CH2—CS), 1.60 (d, J=6.15 Hz, 3H, CH3—CH), 1.44 (s, 18H, t-butyl) ppm; 13C NMR (CDCl3, 500 MHz) δ 170.78 (C═O), 155.52 (C), 135.93 (two C), 127.39 (C), 124.30 (two CH), 59.56 (C), 58.00 (CH), 56.40 (CH2), 54.23 (CH2), 52.82 (CH2), 45.88 (CH3), 37.68 (CH2), 36.50 (CH2), 34.28 (C), 30.21 (CH3), 23.99 (CH3) ppm; FUR(HATR) 2943.89, 1619.92, 1388.67 cm−1; GC-MS (EI) 7.31 min m/z: 419 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].C([Li])CCC.[C:16](=[O:18])=[O:17]>C1COCC1>[C:5]([C:4]1[CH:3]=[C:2]([F:1])[C:9]([C:16]([OH:18])=[O:17])=[C:8]([F:10])[CH:7]=1)#[N:6]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(C(=O)O)c(F)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of 3,5-difluorobenzonitrile (3.48 g, 25 mmol, Fluorochem) in THF (35 ml) was added slowly butyl lithium (1.6M in hexanes) (15.63 ml, 25.00 mmol) at −75° C. The resulting solution was stirred for 1 hr at −70-75° C. Then this solution was poured on freshly crushed dry ice CO2 (44.0 g, 1000 mmol). The contents were stirred at room temperature until dry ice disappearance. The solvent was evaporated off under HV. Then residual organic layer was suspended in water and extracted with ethyl acetate (3×50 ml). The product containing aqueous layer was acidified with aqueous HCl solution and the product was re-extracted in the organic layer with Ethylacetate (4×50 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give a white crystalline solid (2.5731 g, 13.91 mmol, 55.6% yield)
Reaction SMILES: [CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([N:19]=[C:20]=S)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[N:28]([CH2:31][C:32](=[O:34])[CH3:33])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([NH:19][C:20]4[O:34][C:32]([CH3:33])=[CH:31][N:28]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(=O)CN=[N+]=[N-]
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C)o3)nc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 25 %

Procedure:
To a solution of N,N-dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 121B, 45.7 mg, 0.120 mmol) in dioxane (343 μL) was added 1-azidopropan-2-one (14.28 mg, 0.144 mmol) and triphenylphosphine (37.8 mg, 0.144 mmol). The contents of the flask were immersed into a preheated oil bath for 35 min and cooled to room temperature. The residue was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on an Isco 12 g column eluting with 1-10% MeOH/CH2Cl2. The pale yellow solid was taken up in MeOH and further purified by preparative HPLC. N,N-Dicyclopropyl-6-ethyl-1-methyl-4-(5-methyloxazol-2-ylamino)-1,6-dihydro imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide was isolated (10 mg, 25% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:4][C:3]=1[O:21][CH3:22].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][OH:33]>CN(C=O)C>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:19])[CH3:20])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH:31]([CH3:30])[CH2:32][OH:33])=[C:3]([O:21][CH3:22])[CH:4]=3)[C:16]=12
Reactant: OCCCBr
Reactant: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1NC(C)CO
Temperature: 70 °C
Yield: 23.6 %

Procedure:
3-(4-amino-3-methoxyphenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA20d) (30 mg, 0.10 mmol) was dissolved in DMF (0.400 ml). K2CO3 (55 mg, 0.4 mmol) was added and reaction was stirred at 70° C. 3-bromo-1-propanol (0.050 ml, 0.6 mmol) was added and reaction was stirred overnight. Solid K2CO3 was removed by filtration. Solvent was partially removed in vacuo. Sodium citrate (50 ml) was added and reaction was extracted with saturated NaCl and CH2Cl2. Organic phases concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA99 (8.4 mg, 24% yield). ESI-MS (M+H)+ m/z calcd 357.2, found 357.1.
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](S(C)(=O)=O)[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[Cl:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: NCCc1ccccc1Cl
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1nc(NCCc2ccccc2Cl)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 160 °C
Yield: 39.9 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(2-chlorophenyl)ethanamine (300 mg, 1.94 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (150 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.99 (t, J=8 Hz, 2H), 3.52-3.53 (m, 2H), 5.39 (s, 2H), 6.03 (s, 2H), 6.29 (s, 1H), 7.03 (s, 1H), 7.24-7.46 (m, 5H), 7.71 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 11.53 (s, 1H).