Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][C:12]#[N:13])=[O:9])=[CH:6][CH:5]=1.BrBr.[C:18](OCC)(=[O:20])[CH3:19]>BrBr>[CH3:1][O:2][CH2:3][C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH:11]([O:20][CH2:18][CH3:19])[C:12]#[N:13])=[O:9])=[CH:6][CH:5]=1
Reactant: COCc1ccc(C(=O)NCC#N)cc1
Reactant: CCOC(C)=O
Agent: BrBr
Product: CCOC(C#N)NC(=O)c1ccc(COC)cc1
Temperature: 30 °C

Procedure:
A solution of 2-(4-methoxymethylbenzoylamino)acetonitrile (5.0 g) in dry ethyl acetate (40 ml) was treated with a couple of drops of bromine and stirred at 30° C. until initiation of the reaction occurred. The bromine was then added dropwise keeping the temperature at 25°-30° C. After completion of the addition the mixture was filtered through celite, and the filtrate treated with ethanol (5 ml), with stirring, followed by triethylamine (5.0 g), at room temperature. After completion of the addition the mixture was stirred for 5 minutes, filtered through celite, and washed with water, dried over magnesium sulphate and evaporated at less than 30° C., giving a brown oil, (5.0 g). This was purified by preparative HPLC to yield the product as white needles (1.6 g), mpt 99°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][CH:15]=[C:16]([C:18](OCC)=[O:19])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:19][CH2:18][C:16]1[N:17]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[S:14][CH:15]=1
Reactant: CCOC(=O)c1csc(-c2cc(OC)c(OC)c(OC)c2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2nc(CO)cs2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3,4,5-trimethoxyphenyl)thiazole-4-carboxylate (6.9 g) was dissolved in THF (100 mL), and to the solution lithium aluminum hydride (810 mg) was added under an argon atmosphere, and the mixture was stirred at 0° C. for 1 hour. After a small amount of water and then sodium sulfate were added to the reaction mixture, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resultant crude crystals were recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:37][CH2:36][N:11]2[C:12](=[O:35])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=1[CH3:30])=[CH:15][C:14]=3[C:31]([F:34])([F:33])[F:32])=O)(C)(C)C.[ClH:38]>C(OCC)C>[ClH:38].[CH3:30][C:20]1[CH:21]=[C:22]([O:25][C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:35])[N:11]3[CH2:36][CH2:37][NH:8][CH2:9][C@H:10]32)=[C:14]([C:31]([F:34])([F:32])[F:33])[CH:15]=1
Reactant: Cc1cc(OC(F)(F)F)ccc1-c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(OC(F)(F)F)ccc1-c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (11 mg, 0.022 mmol) was added diethyl ether (2 mL) and saturated aqueous hydrochloric acid (1 mL). After 15 min of stirring, the reaction was concentrated, diluted with water and lypholized to give (R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one hydrochloric acid salt (9.7 mg, 97%) as a white solid. MS (ESI) 431.3 (M−Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[C:4]([NH:12][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=2)=[O:22])[CH:3]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Cl)cc2cnccc12
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cc(Cl)cc2cnccc12

Procedure:
Prepared from 7-chloroisoquinolin-5-amine (Description 87) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 380 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=1[O:8][Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=1[OH:8]
Reactant: CCOC(=O)CCc1cc(Br)c(O[Si](C)(C)C(C)(C)C)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(Br)c(O)c(OC)c1
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
A solution of Intermediate 18 (750 mg) in THF (50 ml) was added with a 1 M solution of tetrabutylammonium fluoride in THF (5 ml, TCI), and stirred for 1.5 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (30 ml), and extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (Intermediate 19, 542 mg).
Reaction SMILES: C(OC1C(F)=CC=C2C=1C(CCN(C)C)=CN2)C1C=CC=CC=1.[CH2:24]([N:26]1[C:34]2[C:29](=[C:30]([OH:36])[CH:31]=[C:32]([F:35])[CH:33]=2)[C:28]([CH:37]2[CH2:42][CH2:41][CH2:40][N:39]([C:43](OC(C)(C)C)=O)[CH2:38]2)=[CH:27]1)[CH3:25]>>[CH2:24]([N:26]1[C:34]2[CH:33]=[C:32]([F:35])[CH:31]=[C:30]([OH:36])[C:29]=2[C:28]([CH:37]2[CH2:42][CH2:41][CH2:40][N:39]([CH3:43])[CH2:38]2)=[CH:27]1)[CH3:25]
Reactant: CCn1cc(C2CCCN(C(=O)OC(C)(C)C)C2)c2c(O)cc(F)cc21
Agent: CN(C)CCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Product: CCn1cc(C2CCCN(C)C2)c2c(O)cc(F)cc21
Yield: 22 %

Procedure:
Following the procedure (step 6, scheme 1) used to prepare compound 1-7a, compound 38-5 gave compound 38-6 (20 mg, 22%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 9.91 (s, 1H), 6.92 (s, 1H), 6.63 (dd, J=10.2, 2.1 Hz, 1H), 6.14 (dd, J=11.5, 2.1 Hz, 1H), 3.98 (q, J=7.1 Hz, 2H), 3.31 (m, 1H), 3.02 (d, J=10.1 Hz, 1H), 2.71 (s, 1H), 2.14 (s, 3H), 2.01-1.42 (m, 5H), 1.25 (m, J=7.2 Hz, 4H). LCMS: calc 276.2 and found: 277.1 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40]([F:45])([CH2:43]O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40]([CH2:43][N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])([F:45])[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-ylmethyl}-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione and 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester following General Procedure J.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][C:33]=1[C:34]([N:36]([O:38][CH3:39])[CH3:37])=[O:35])[CH2:12][O:13][CH2:14][C@@H:15]1[CH2:17][C@@H:16]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].ClC1[N:52]=[CH:51][C:50]([Cl:53])=[CH:49][N:48]=1>C(Cl)Cl.O>[Cl:53][C:50]1[CH:49]=[N:48][C:24]([N:21]2[CH2:20][CH2:19][CH:18]([C@H:16]3[CH2:17][C@H:15]3[CH2:14][O:13][CH2:12][C:11]3[CH:31]=[CH:32][C:33]([C:34]([N:36]([O:38][CH3:39])[CH3:37])=[O:35])=[C:9]([F:8])[CH:10]=3)[CH2:23][CH2:22]2)=[N:52][CH:51]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CON(C)C(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
TFA (1 mL) was added to a solution of product from step B (35 mg, 0.078 mmol) in DCM (1 mL) and the resulting mixture stirred at RT for 15 min. The mixture was evaporated and the residue dissolved in DMF (1 mL) and Cs2CO3 (76 mg, 0.233 mmol) and 2,5-dichloropyrimidine (13.89 mg, 0.093 mmol) added. The resultant mixture was stirred at RT overnight, diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent EtOAc/hexanes 0-100%) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 8.02 (s, 1H), 7.44 (m, 1H), 7.17 (d, 1H), 7.13 (d, 1H), 4.72-4.62 (m, 2H), 4.61 (d, 1H), 4.55 (d, 1H), 3.66-3.53 (m, 4H), 3.53-3.47 (m, 1H), 3.38 (br s, 3H), 2.89-2.81 (m, 2H), 1.97 (d, 1H), 1.93 (d, 1H), 1.43-1.31 (m, 2H), 1.29-1.20 (m, 1H), 1.11-1.02 (m, 1H), 0.81-0.69 (m, 2H), 0.09-0.04 (m, 1H). MS (ESI) m/z 463 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][O:17][CH3:18])[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1.[N+](=[CH2:32])=[N-]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:19]([O:21][CH3:32])=[O:20])[CH2:15][CH2:16][O:17][CH3:18])[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1
Reactant: C=[N+]=[N-]
Reactant: COCCC(=NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Product: COCCC(=NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1)C(=O)OC

Procedure:
In the manner given in Example 10, 7-bromo-2-[(1-carboxy-3-methoxypropylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-bromo-2-[[1-(methoxycarbonyl)-3-methoxypropylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O)=CC=1.[OH:28][CH:29]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH2:26]([O:28][CH:29]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCOC(CCCCCC)CCCCCCCCCCC(=O)OCC
Temperature: 81 °C
Reaction time: 6 h

Procedure:
Dissolve 10 mmol palmityl toluene-4-sulfonate, 10 mmol ethyl 12-hydroxystearate, 10 mmol anhydrous potassium carbonate and 0.5 mmol sodium iodide in 100 ml dry acetonitrile and heat to 81° C. with stirring for 6 hours. The reaction is cooled to room temperature. The solvent is evaporated and the products are suspended in MTBE and washed with 3×50 ml cold water. The solvent is evaporated to yield ethyl 12-palmityloxy-stearate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11](OCC)=[O:12])[CH:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[NH:30][CH:31]=[CH:32][C:25]=34)=[C:19]([F:33])[CH:18]=2)[N:3]=1.[B-].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[NH:30][CH:31]=[CH:32][C:25]=34)=[C:19]([F:33])[CH:18]=2)[N:3]=1
Reactant: CCOC(=O)CCCc1cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)nc(N)n1
Agent: [B-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(CCCCO)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
300 mg (0.67 mmol) of 4-(2-amino-6-{[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amino}pyrimidin-4-yl)butan-1-ol (from example 132) are suspended in 15 ml of ethanol, and 253 mg (6.66 mmol) of sodium borohydrate are added a little at a time at RT. The mixture is stirred at RT for 24 hours and then concentrated, and ethyl acetate and water are added. The organic phase is dried over sodium sulfate. The product is purified by column chromatography (silica gel 60; gradient column, mobile phase: DCM:methanol=9:1 to 3:1). 133 mg (27%) of the starting material are recovered. The product fraction is re-purified by preparative HPLC. This gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH:14][CH:15]1[CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]3[CH2:21][NH:20][C:19](=[O:28])[C:18]=3[C:17]=2[CH2:16]1.[CH3:29]CN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:29])[CH:15]1[CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]3[CH2:21][NH:20][C:19](=[O:28])[C:18]=3[C:17]=2[CH2:16]1
Reactant: O=C1NCc2ccc3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCCc1c[nH]c2ccc(F)cc12)C1COc2ccc3c(c2C1)C(=O)NC3
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of (3) (52 mg, 0.137 mmol) and Me3OBF4 (40 mg, 0.274 mmol) in methylene chloride (5 ml) was added Hunig's base (40 μl, 0.274 mmol). The reaction mixture was stirred at 50° C. for 2 hr, then diluted with 100 ml of methylene chloride. It was washed with H2O, saturated NaCl. The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel eluting with (80% EtOAc/Hexane) to give the title compound, which was treated with 1 equivalent of etherate HCl to give HCl salt. MS (ES) m/z 394.1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[N:23]=3)[C:19]([Cl:29])=[CH:18][N:17]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.O1CCOCC1>>[NH2:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[N:23]=3)[C:19]([Cl:29])=[CH:18][N:17]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl(trans-4-(5′-chloro-6-fluoro-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methylcarbamate (390 mg, 0.897 mmol), 4M HCl in Dioxane (5604 μl, 22.42 mmol) reaction mixture was stirred at ambient temperature for 1 hr. The crude reaction mixture mixture was concentrated, and then dried under high vacuum to a constant mass giving 335 mg of the title compound as a HCL salt. LCMS (m/z): 335.1 (MH+), retention time=0.51 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.B>O1CCCC1>[OH:15][CH2:14][C:11]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (40 g, 131 mmol) in tetrahydrofuran (131 mL) at room temperature was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 131 mL, 131 mmol). There was effervescence and the substrate quickly went into solution. The reaction was stirred at room temperature for 3 days. The reaction was cooled to 0° C. and quenched by the cautious addition of 1 M sodium hydroxide. The reaction was diluted with diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Trituration with 10% EtOAc/Hex (300 mL) gave a white powder which was collected by filtration to give 36.9 g (97%). 1H-NMR (CD3OD, 500 MHz) δ 7.35-7.43 (m, 4H), 7.24-7.26 (m, 1H), 3.78-3.85 (m, 2H), 3.49 (s, 2H), 2.97 (m, 2H), 2.17-2.21 (m, 2H), 1.77-1.87 (m, 2H), 1.46 (s, 9H). Mass spec.: 292.17 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>CC(C)=O>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: Oc1cccc(F)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(COc2cccc(F)c2)cc1
Yield: 87.2 %

Procedure:
A mixture of 4-(bromomethyl)benzonitrile (23.50 g, 120.0 mmol), K2CO3 (55.20 g, 400.0 mmol) and 3-fluorophenol (11.21 g, 100.0 mmol) were heated at reflux in acetone (400 mL) (16 h). The volatiles were evaporated and the residue was diluted with CH2Cl2 (300 mL). The organic layer was washed with H2O (300 mL), dried (MgSO4) and concentrated in vacuo to give white needles (19.81 g, 87%): Rf=0.40 (9/1 hexanes/ethyl acetate); mp 69-70° C.; 1H NMR (CDCl3) δ 5.02 (s, CH2O), 6.56-6.67 (m, 3 ArH), 7.16 (q, J=7.7 Hz, 1 ArH), 7.45 (d, J=7.1 Hz, 2 ArH), 7.59 (d, J=8.1 Hz, 2 ArH); 13C NMR (CDCl3) δ 60.1 (CH2O), 102.8 (d, J=24.4 Hz, C2′ or C4′), 108.3 (d, J=21.1 Hz, C4′ or C2′), 110.4 (d, J=2.8 Hz, C6′), 111.9 (ArC), 118.6 (CN), 127.5 (ArC), 130.4 (d, J=9.7 Hz, C5′), 132.4, 141.9 (2 ArC), 159.4 (d, J=10.8 Hz, C1′), 163.6 (d, J=244.2 Hz, C3′); LRMS (M+Na+) (ESI+) 250.0 [M+Na+] (calcd for C14H10NONa+ 250.0).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:35][C:36]([F:57])([F:56])[O:37][C:38]1[CH:47]=[C:46]2[C:41]([CH:42]=[C:43](OS(C(F)(F)F)(=O)=O)[N:44]=[CH:45]2)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:64]>COCCOC.O.C(Cl)Cl.C(OCC)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>[ClH:64].[ClH:64].[ClH:64].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([C:43]4[N:44]=[CH:45][C:46]5[C:41]([CH:42]=4)=[CH:40][CH:39]=[C:38]([O:37][C:36]([F:35])([F:57])[F:56])[CH:47]=5)[C:22]([NH2:34])=[N:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: O=S(=O)(Oc1cc2ccc(OC(F)(F)F)cc2cn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2ccc(OC(F)(F)F)cc2cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (75 mg, 0.16 mmol), trifluoromethanesulfonic acid 7-trifluoromethoxyisoquinolin-3-yl ester (69 mg, 0.19 mmol), potassium carbonate (66 mg, 0.48 mmol), Pd(PPh3)4 (18 mg, 0.016 mmol) in DME (1.5 mL) and H2O (0.5 mL) was evacuated and refilled with N2 (3×), then it was heated at 100° C. for 30 min using the microwave reactor. The reaction mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex.:EtOAc=30:70→15:85) to give a yellow solid. This material was dissolved in DCM (2 mL) and treated with 1M HCl in diethyl ether (3 mL). The resulting mixture was stirred at room temperature overnight. The title compound was collected by filtration as a yellow solid and washed with DCM. MS (ES+): m/z=455.12 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)=[O:8])=[CH:5][CH:4]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](N)=[CH:28][CH:29]=2)C=C1.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.CN(C)C1C=CC(C(O)=O)=CC=1.C(Cl)CCl>CN(C=O)C.O>[NH2:22][C:30]1[CH:25]=[CH:26][C:27]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:20][CH:19]=4)=[CH:18][CH:17]=3)[CH:13]=[CH:14]2)=[CH:28][CH:29]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc3[nH]ccc3c2)cc1
Agent: CN(C)c1ccc(C(=O)O)cc1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)Nc2ccc3c(ccn3-c3ccc(N)cc3)c2)cc1

Procedure:
Compound 369 was prepared according to the general procedure described in Scheme IV. Preparation of 4-(dimethylamino)-N-(1H-indol-5-yl)benzamide: 1H-indol-5-amine (200 mg, 1.51 mmol), hydroxybenzotriazole (204 mg, 1.51 mmol), triethylamine (0.23 mL, 1.66 mmol), and 4-(dimethylamino)benzoic acid (275 mg, 1.66 mmol) were taken up in DMF (7.5 mL) and stirred. EDC (319 mg, 1.66 mmol) was added to the solution last. After the addition, the solution was stirred at room temperature for 4 h. Water was then added to the solution and stirred for 10 min. The formed precipitate was filtered and washed well with water, followed by hexanes. The grayish solid was dried under vacuum to give 393 mg (93%) of the product.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:4]2[C@@H:5]([NH:27]C(=O)OC(C)(C)C)[CH2:6][CH2:7][CH2:8][C@@H:9]([CH3:26])[C:10](=[O:25])[NH:11][C:12]3[C:17]([C:18]=1[N:19]=2)=[CH:16][CH:15]=[C:14]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH:13]=3.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C@@H:5]1[C:4]2=[N:19][C:18](=[C:2]([Cl:1])[N:3]2[CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[C:17]2[C:12](=[CH:13][C:14]([NH:20][C:21](=[O:22])[O:23][CH3:24])=[CH:15][CH:16]=2)[NH:11][C:10](=[O:25])[C@H:9]([CH3:26])[CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](NC(=O)OC(C)(C)C)c1nc-2c(Cl)n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](N)c1nc-2c(Cl)n1COCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
135I (0.476 g, 0.765 mmol) was treated with TFA (2.95 mL, 38.2 mmol) in DCM (15 mL). After 1 hour, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and washed with 1.5M potassium phosphate. The organic layer was washed further with brine, dried over sodium sulfate, filtered, and concentrated. This material was carried forward as is. MS (ESI) m/z: 522.3 (M+H)+.