Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]#[N:16].[C:17]1([S:23][CH2:24][N:25]=[N+:26]=[N-:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:27]=[N:26][N:25]([CH2:24][S:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]=1[NH2:16]
Reactant: N#CCc1ccccc1F
Reactant: [N-]=[N+]=NCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1c(-c2ccccc2F)nnn1CSc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
To a stirred suspension of potassium carbonate (19.5 g, 141 mmol) in dry dimethylsulfoxide (100 ml) under nitrogen was added 2-fluorophenylacetonitrile (5.9 ml, 46 mmol). The reaction was stirred for 5 minutes at which time azidomethyl phenyl sulfide (5 ml, 35.3 mmol) was added dropwise. The resulting yellow reaction mixture was stirred at room temperature for 16 hours before slow addition to distilled water (2000 ml) with vigorous stirring. The aqueous mixture was extracted with ethyl acetate (4×500 ml) and the combined organic extracts were washed with brine (500 ml), dried (Na2SO4) and the solvent removed in vacuo. The resultant brown oil was purified by flash chromatography (25% EtOAc/isohexane) and the product crystallised from diethyl ether to furnish 5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-ylamine (3.04 g, 29%) as a pale yellow solid. δH (400 MHz, CDCl3) 4.10 (2H, br s, NH2), 5.55 (2H, s, PhSCH2), 7.11 (1H, ddd, J=11.5, 8.2 and 1, ArH), 7.22-7.32 (5H, m, ArH), 7.39-7.41 (2 H, m, ArH), 7.89 (1H, td, J=7.5 and 2.0, ArH); m/z (ES+) 301 (M+H+).
Reaction SMILES: [N+:1]([N:4]1[C:8]2=[C:9]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:10]3[CH:11]=[CH:12][C:13]([N:48]=3)=[C:14]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:15]3[N:19]([N+:20]([O-])=O)[C:18]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:24]4[N:35]=[C:27]([C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:5]1[CH:6]=[CH:7]2)[CH:26]=[CH:25]4)=[CH:17][CH:16]=3)([O-])=O>C1(C)C=CC=CC=1.[Ru]>[NH2:20][N:19]1[C:15]2=[C:14]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:13]3[CH:12]=[CH:11][C:10]([N:48]=3)=[C:9]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:8]3[N:4]([NH2:1])[C:5]([C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:27]4[N:35]=[C:24]([C:23]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)=[C:18]1[CH:17]=[CH:16]2)[CH:25]=[CH:26]4)=[CH:6][CH:7]=3
Reactant: O=[N+]([O-])n1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3[N+](=O)[O-])C=C1
Agent: [Ru]
Solvent: Cc1ccccc1
Product: Nn1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3N)C=C1
Temperature: 25 °C

Procedure:
Dinitrotetraphenylporphyrin (2.0 g 2.84 mol) was added to a hydrogenation flask (500-ml) and dissolved in dry toluene (200-ml). To this solution was added the catalyst about 10% ruthenium on alumina pellets (4.0 g, from Engelhard Industries, Iselin, N.J.). After evacuation, and flushing with hydrogen, the reduction was performed at 70° at 60 psi for 8-hr. Next, the flask was cooled to ambient temperature, filtered in the dark to remove the catalyst. The solid catalyst was washed repeatedly with toluene to obtain the product. The organic solvent was removed under reduced pressure in the dark at 50° C. to produce the crude solid residue. This residue showed one spot above the two spots near the base line for the product. An additional brown spot very close to the starting material was also observed. The residue was 1.6 g
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:18]([Si:20]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:21][CH2:22][O:23][CH2:24]Cl)[CH3:19].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH2:26][CH3:27])([CH2:18][CH3:19])[CH2:28][CH3:29])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC[Si](CC)(CC)CCOCCl
Reactant: Oc1cccnc1Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)CCOCOc1cccnc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 2-bromo-3-hydroxypyridine (15 g, 0.0862 mol) in chloroform (260 mL), ethyldiisopropylamine (18 mL, 0.103 mol) and 2-(triethylsilyl)ethoxymethyl chloride (16.7 mL, 0.0948 mol) were added at 0° C. After the mixture was stirred at room temperature for 2 hours, water (50 mL) was added thereto and the precipitated insoluble materials were filtered off. The organic layer of the filtrate was separated, washed with water, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2-bromo-3-[2-(triethylsilyl)ethoxymethoxy]pyridine (20.3 g, 77%) as a light-yellow oil.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.Cl.[NH2:21][CH2:22][C@H:23]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:27]([O:26][C:24](=[O:25])[C@@H:23]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:22][NH:21][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][NH:7][C:3]2[S:2][CH:6]=[CH:5][N:4]=2)=[CH:19][CH:18]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1ccc(OCCNc2nccs2)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCNc2nccs2)cc1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acid 24-5 (160 mg, 0.60 mmol), amine 2-1 (215 mg, 0.60 mmol), EDC (140 mg, 0.73 mmol), HOBT (98 mg, 0.73 mmol), and NMM (235 μL, 2.1 mmol) were combined in 3 mL DMF at -15°. After stirring at RT for 16 h, the reaction was diluted with EtOAc, washed with water, sat. NaHCO3 and brine, dried, concentrated, and purified by flash chromatography (silica, 70% EtOAc/hexane) providing 24-6 as an off-white solid. Rf 0.54 (silica, EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17].[C:19](Cl)(=O)[CH3:20].C(Cl)(=O)/C=C/C>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][O:14][NH:15][C:16](=[O:18])/[CH:17]=[CH:19]/[CH3:20]
Reactant: COc1ccc2ccccc2c1CONC(C)=O
Reactant: CC(=O)Cl
Agent: C/C=C/C(=O)Cl
Product: C/C=C/C(=O)NOCc1c(OC)ccc2ccccc12

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 7, but replacing, in the acylation step, acetic acid chloride with crotonic acid chloride, the title compound is obtained.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C:7]1[O:8][C:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][C:10]=2[N:11]=1)=O>CO.C1COCC1.[NH4+].[Cl-]>[CH3:21][C:18]([O:17][C:15]([N:13]1[CH2:14][C:9]2[O:8][C:7]([CH2:5][OH:4])=[N:11][C:10]=2[CH2:12]1)=[O:16])([CH3:19])[CH3:20]
Reactant: COC(=O)c1nc2c(o1)CN(C(=O)OC(C)(C)C)C2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2nc(CO)oc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Lithium borohydride (0.015 g, 0.72 mmol) was added to a stirred solution of 4,6-dihydro-5H-pyrrolo[3,4-d]oxazole-2,5-dicarboxylic acid 5-(1,1-dimethylethyl) 2-methyl ester (0.064 g, 0.24 mmol) in a mixture of MeOH (0.6 mL) and THF (1 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes, diluted with a saturated solution of NH4Cl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 4,6-dihydro-2-(hydroxymethyl)-5H-pyrrolo[3,4-d]oxazole-5-carboxylic acid 1,1-dimethylethyl ester (0.055 g, 96% yield) as a clear oil that was used in the next step without further purification. C11H16N2O4 LCMS: Rt 1.29, m/z 241 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[N:27]([C:28]5[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=5[CH3:35])[NH2:31])[CH:26]=[CH:25][N:23]4[N:24]=3)[CH:17]=[N:16]2)=[CH:12][CH:11]=1.[N:38]1([C:44]2[CH:45]=[C:46]([CH:50]=[C:51]([S:53]([F:58])([F:57])([F:56])([F:55])[F:54])[CH:52]=2)[C:47](O)=[O:48])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[OH-].[Na+]>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[N:27]([C:28]5[CH:29]=[C:30]([NH:31][C:47](=[O:48])[C:46]6[CH:50]=[C:51]([S:53]([F:58])([F:54])([F:55])([F:56])[F:57])[CH:52]=[C:44]([N:38]7[CH2:43][CH2:42][O:41][CH2:40][CH2:39]7)[CH:45]=6)[CH:32]=[CH:33][C:34]=5[CH3:35])[CH:26]=[CH:25][N:23]4[N:24]=3)[CH:17]=[N:16]2)=[CH:36][CH:37]=1
Reactant: O=C(O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)ccn4n3)cn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(N7CCOCC7)cc(S(F)(F)(F)(F)F)c6)ccc5C)ccn4n3)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
82 mg (0.16 mmol) of the compound of Example 8A, 59 mg (0.18 mmol) of the compound of Example 18A and 73 mg (0.192 mmol) of HATU were dissolved in 1 ml of DMF. 53 μl (0.48 mmol) of 4-methylmorpholine were then added. After the reaction mixture had been stirred at RT for 16 h, 10 ml of 0.1 M aqueous sodium hydroxide solution were added, whereupon the product precipitated as a solid. The mixture was stirred for another 10 min, and the product was then filtered off with suction, washed with water and dried under high vacuum. This gave 104 mg (70% of theory, 77% pure) of the title compound as a greyish-brown solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]1[C:19]2[C@@H:20]3[C@H:25]([CH2:26][CH2:27][C:18]=2[CH:17]=[CH:16][CH:15]=1)[NH:24][CH2:23][CH2:22][CH2:21]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@@H:20]([C:19]5[C:14]([F:13])=[CH:15][CH:16]=[CH:17][C:18]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Fc1cccc2c1[C@H]1CCCN[C@H]1CC2
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3c(F)cccc3CC[C@@H]21
Yield: 75 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-10-fluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 75% of theory; LC (method 1): tR=2.66 min; Mass spectrum (ESI+): m/z=350 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](C1C=CC(C2CC(OC)OC2OC)=CC=1)#[N:37]>>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:36]#[N:37])=[CH:33][CH:34]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1CC(c2ccc(C#N)cc2)C(OC)O1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(C#N)cc2)c1)C(C)(C)C
Yield: 41 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(1,7-diaza4-oxa-8-oxo-tricyclo-[9.6.1.012,17]-octadeca-11(18), 12,14,16-tetraen-9S-yl)-3(R)-(-3-phenyl-1H-pyrrol-1-yl)-succinamic acid benzyl ester, crude 3(R)-amino-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl ester trifluroacetate salt (prepared as described in Example 1(b)) and 3-(4-cyanophenyl)-2,5-dimethoxy-tetrahydrofuran were condensed. Drying the crude product via azeotrope with benzene gave 1.70 g (41%) of 3(R)-[-3-(4-cyanophenyl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester as a yellow solid, mp 102-4° C. 1H NMR (CDCl3): δ 7.60-7.55 (m, 4H), 7.30-7.25 (m, 5H), 7.12 (t, 1H, J=2.2 Hz), 6.80 (t, 1H, J=2.5 Hz), 6.56 (t, 1H, J=2.8 Hz), 6.32 (d, 1H, J=8.7 Hz), 5.60 (d, 1H, J=5.0 Hz), 5.18-5.05 (m, 3H), 4.05 (d, 1H, J=9.0 Hz), 3.38 (dd, 1H, J=5.9, 17.0 Hz), 3.08 (dd, 1H, J=8.7, 16.8 Hz), 2.76 (d, 3H, J=5.0 Hz), 0.92 (s, 9H). IR: 3310, 2958, 2227, 1736, 1648, 1547 cm−1. HRFABMS: Calculated for C29H32N4O4Cs (MH+Cs+): 633.1478. Found: 633.1452. Anal. Calculated for C29H32N4O.0.4C6H6: C, 70.91; H, 6.52; N, 10.53. Found: C, 70.97; H, 6.15; N, 10.26.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]CCCC)=[C:16]([C:25]#[N:26])[C:15]=2[C:27]#[N:28])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>O>[C:25]([C:16]1[C:15]([C:27]#[N:28])=[C:14]([CH2:13][CH2:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)[CH:19]=[CH:18][C:17]=1[OH:20])#[N:26]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(OCCCC)c(C#N)c2C#N)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(O)c(C#N)c2C#N)CC1
Temperature: 150 °C
Yield: 32 %

Procedure:
A finely powdered mixture was prepared from 2.2 g of 2-(trans-4-pentylcyclohexyl)-1-(2,3-dicyano-4-butyloxyphenyl)ethane, 1.4 g of anhydrous aluminum chloride and 0.3 g of sodium chloride and this mixture was heated to 150° C. on an oil-bath for 40 minutes under anhydrous conditions. The cooled mixture was treated with 250 ml of water and extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with 250 ml of water, dried over magnesium sulphate and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 4:1) gave 0.6 g of 2,3-dicyano-4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol; m.p. 100°-102° C.
Reaction SMILES: [N:1]1[C:9](N)=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[CH3:18][Si:19]([CH3:26])([CH3:25])[NH:20][Si:21]([CH3:24])([CH3:23])[CH3:22]>>[CH3:18][Si:19]([N:20]([Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2)([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: C[Si](C)(C)N(c1ncnc2nc[nH]c12)[Si](C)(C)C

Procedure:
Bis-trimethylsilyladenine was prepared by combining 7 g of adenine and 109 ml of hexamethyldisilazane with 250 mg of ammonium sulfate and heating the mixture at 110°-115° C. for 8 hours. The solution was refluxed for an additional 30 minutes and the excess hexamethyldisilazane subsequently removed and 14.5 g of the bis-trimethylsilyladenine were reconstituted in 3 ml of anisole. 1.58 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-α-methanesulfonate were reacted with the bis-trimethylsilyladenine solution at 105° C.-110° C. for 24 hours. HPLC analysis confirmed completion of the reaction.
Reaction SMILES: C([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[C:31](O)=[O:32])C1C=CC=CC=1.S(Cl)(Cl)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)(Cl)Cl>[CH2:20]([C@@H:18]1[CH2:19][N:14]2[C:15]([C:16]3[NH:8][C:9]([C:31]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:32])=[N:10][C:11]=3[N:12]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:27])=[N:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C(=O)O)n2Cc1ccccc1
Reactant: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C(=O)N3CCCCC3)nc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Compound 47a (70 mg, 0.158 mmol) obtained in Example 47 was dissolved in chloroform (2 mL), to the solution was added thionyl chloride (40 μL, 0.548 mmol, 3.4 equivalents), and the mixture was stirred at 60° C. for 30 minutes. To the reaction solution was added piperidine (320 μL, 3.24 mmol, 20 equivalents) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and directly purified by silica gel column chromatography (chloroform:methanol=98:2). Thereafter, the title compound (17 mg, 26%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]([CH3:31])([CH3:30])[CH2:12][C:13]1[N:14]([CH2:27][CH2:28][CH3:29])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[NH2:26].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:26][C:17]1[C:16]2=[N:15][N:14]([CH2:27][CH2:28][CH3:29])[C:13]([CH2:12][C:11]([NH:10][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])([CH3:31])[CH3:30])=[C:25]2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Cyclohexanecarbonyl chloride (401 μL, 3.00 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 892 mg, 3.00 mmol) and triethylamine (627 μL, 4.5 mmol) in dichloromethane (26.7 mL). After 3 hours at 0° C., the solution was stirred for 2 days at ambient temperature. More triethylamine (697 μL) and cyclohexanecarbonyl chloride (602 μL) was added. After 30 minutes, 2 M aqueous sodium carbonate was added to the solution. The mixture was extracted with chloroform four times. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Methanol (20 mL) and concentrated hydrochloric acid (2 mL) were added. The solution was heated at reflux for 4 hours, then left to stand at ambient temperature overnight, then heated at reflux again for brief periods of time during the next 2 days. In all, the solution was heated at reflux for a total of 7 hours. After cooling to ambient temperature, 2 M aqueous sodium carbonate was added to adjust the mixture to pH 10-11. The mixture was concentrated under reduced pressure to remove the methanol. Water was added and a solid was isolated from the mixture by filtration. The solid was washed with water. Chloroform was added to the solid, and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by IFC. The appropriate fractions were combined and concentrated to a white solid that was recrystallized from 50% ethyl acetate/hexanes. The crystals were isolated by filtration and dried to yield 896 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide as a white solid, mp 190-191° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[S:43]([NH:46][C:47]1[C:48]([O:62][CH3:63])=[N:49][CH:50]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:52]=1)(=[O:45])=[O:44].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[S:43]([NH:46][C:47]1[C:48]([O:62][CH3:63])=[N:49][CH:50]=[C:51]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:13])=[C:4]([C:20]3[O:21][C:22]([CH2:25][N:26]4[CH2:27][CH2:28][N:29]([CH:32]([CH3:33])[CH3:34])[CH2:30][CH2:31]4)=[CH:23][N:24]=3)[CH:3]=2)[CH:52]=1)(=[O:45])=[O:44]
Reactant: CC(C)N1CCN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
To a solution of 6-chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (0.2 g, 0.40 mmol) and 2,4-difluoro-N-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.222 g, 0.52 mmol) in 1,4-dioxane (2 ml) was added chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.2 g, 0.020 mmol), potassium phosphate tribasic (0.255 g, 1.20 mmol) and water (0.2 ml). The reaction mixture was heated to 120° C. with stirring for 3 h under microwave irradiation then filtered through a silica SPE, eluting with methanol. The solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous extracted with further dichloromethane (2×2 ml). The combined organics were concentrated under a stream of nitrogen and the residue purified using silica gel chromatography, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were evaporated in vacuo to give the title compound as a brown solid (0.081 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)c(F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3,4-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:34][CH3:35])=[C:16]([CH:23]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([C:21]#[N:22])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:34][CH3:35])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CNC1
Reaction time: 1 h

Procedure:
The tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate (0.35 g, 0.73 mmol) (Step 7, peak 1) was dissolved in methylene chloride (3.0 mL) and trifluoroacetic acid (1.0 mL) at room temperature. After stirring for 1 h the reaction was complete by LC/MS. The reaction was concentrated in vacuo to give 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-methoxy-6-methylbenzonitrile (bis(trifluoroacetate) as a viscous amber oil (0.50 g, 100%). LCMS calculated for C20H24N7O (M+H)+: m/z=378.2; found: 378.2.