Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>CN(C=O)C.O>[F:27][C:26]([F:28])([F:29])[O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a dried flask charged with tert-butyl 4-hydroxypiperidine-1-carboxylate (3.60 g, 17887 μmol) was added dry DMF (40 mL) and the resulting solution cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (748 mg, 18781 μmol) in two portions 5 min apart. The reaction mixture was stirred for 1 hr and allowed to warm to RT over that time. The resulting suspension was cooled in an ice water bath prior to the addition of a solution of 1-(bromomethyl)-4-(trifluoromethoxy)benzene (5018 mg, 19676 μmol) in DMF (5 mL) via syringe. The resulting reaction mixture was allowed to slowly warm to RT while stirring for 15 h. The resulting pale yellow suspension was carefully diluted with water (about 150 mL) and extracted 2× with EtOAc. The combined organics were dried with Na2SO4, filtered and concentrated under reduced pressure. The material was purified through silica gel column chromatography ramping ethyl acetate in hexanes from 0% to 10% over 5 mins, then remaining at 10% for 10 min, then ramping to 50% over 5 min providing tert-butyl 4-(4-(trifluoromethoxy)benzyloxy)-piperidine-1-carboxylate (5 g) as a white crystalline solid upon drying.
Reaction SMILES: [NH2:1][CH:2]([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>C(#N)C>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:1][CH:2]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(COCC(N)Cn2ccnc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(COCc2ccc(OC)cc2)Cn2ccnc2)cc1
Yield: 3.6 %

Procedure:
A solution of 1-[2-amino-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (1.70 g, 0.0065M) in dry acetonitrile (10 ml) containing triethylamine (0.5 ml) was treated with 4-methoxybenzyl chloride (1.12 g, 0.0072M) and heated under reflux for 18 hours under a stream of dry nitrogen. The solvent was evaporated off under reduced pressure and the residue was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and dried (MgSO4). The solvent was evaporated off under reduced pressure to give the crude product as an oil which was further purified by chromatography (silica gel), 10% ethanol in chloroform) to give N-[(4-methoxyphenyl)methyl]-α-[[(4-methoxyphenyl)methoxy]methyl]-1H-imidazole-1-ethanamine (0.09 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10]([OH:12])=O)[C:6]=1[CH3:7].[F:44][C:45]([F:57])([F:56])[C:46]1[CH:55]=[C:54]2[C:49]([CH2:50][CH2:51][NH:52][CH2:53]2)=[CH:48][CH:47]=1>>[CH2:35]([N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:52]2[CH2:51][CH2:50][C:49]3[C:54](=[CH:55][C:46]([C:45]([F:44])([F:57])[F:56])=[CH:47][CH:48]=3)[CH2:53]2)=[O:12])[N:4]=1)=[O:43])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)c(C)c1Cl
Yield: 72.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 93B, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 21 mg, 0.034 mmol) and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (7 mg, 0.037 mmol) were converted to the title compound (20 mg, 71%) following purification by preparative HPLC. 1H NMR (1:1 CD3OD:CDCl3, 1.5:1 mixture of amide rotamers) δ 8.69-8.58 (m, 1H), 8.19-8.13 (m, 1H), 8.08-8.02 (m, 2H), 8.01-7.97 (m, 1H), 7.95-7.91 (m, 1H), 7.90-7.86 (m, 1H), 7.60-7.54 (m, 2H), 7.45-7.34 (m, 2.5H), 7.28-7.23 (m, 1H), 7.17-7.14 (m, 0.5H), 4.89-4.64 (m, 1.5H), 4.52 (s, 1H), 4.16-4.02 (m, 0.5H), 3.70-3.34 (m, 2.5H), 3.24-2.75 (m, 4.5H), 2.28 (s, 2H), 2.23 (s, 1H), 1.51-0.93 (m, 8H), 0.87 (dt, J=17.8, 7.4 Hz, 3H), 0.75 (t, J=7.4 Hz, 2H), 0.64 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 808.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([O-:24])=[O:23].[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:10]2[CH2:9][NH2+:8][CH2:11]2)=[CH:18][CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(Cc2ccc(Cl)cc2)C1
Solvent: ClCCl
Product: Clc1ccc(CC2C[NH2+]C2)cc1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(4-Chloro-benzyl)-azetidine-1-carboxylic acid tert-butyl ester (1.61 g, 5.71 mmol) in dichloromethane (20 ml) is treated with trifluoroacetic acid (20 ml) and stirred at ambient temperature for 1 hour. The reaction mixture is evaporated and then re-suspended in toluene and evaporated to dryness to afford 3-(4-Chloro-benzyl)-azetidinium trifluoroacetate salt. [MH]+ of free base 182.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:60])[C:34]([CH3:59])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[CH3:30][O:31][C:32]1[C:33](=[O:60])[C:34]([CH3:59])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)=[C:46]([CH:50]=2)[C:47]([NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3cc(OC)c(OC)c(OC)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 18 %

Procedure:
3,4,5-Trimethoxyaniline (0.260 g, 1.42 mmol), triethylamine (0.144 g, 1.42 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.240 g, 1.42 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.200 g, 0.473 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.085 mmol, 18%).
Reaction SMILES: N1[C:6]2=[CH:7][CH:8]=[N:9][C:5]2=C(C(N)=O)N=N1.[C:13](N)(=O)C1C=CC=CC=1.[C:22]([O:27][CH3:28])(=[O:26])/C=C/C.S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O>>[CH3:28][O:27][C:22]([C:7]1[C:6]([CH3:13])=[CH:5][NH:9][CH:8]=1)=[O:26]
Reactant: NC(=O)c1nn[nH]c2ccnc1-2
Reactant: C/C=C/C(=O)OC
Reactant: NC(=O)c1ccccc1
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Product: COC(=O)c1c[nH]cc1C

Procedure:
WO 00/71129 describes the preparation of 1,4-dihydro-5-alkyl-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylates, key intermediates in the synthesis of pyrrolotriazine carboxamide and benzamide compounds of formula I, by reacting a Michael acceptor such as methyl crotonate with an anion of tosylmethyl isocyanide (TosMIC) to give 4-methylpyrrole-3-carboxylic acid methyl ester. The resulting 4-methylpyrrole-3-carboxylic acid methyl ester is acylated with trichloroacetyl chloride in the presence of aluminum chloride to afford 2-trichloroacetyl-3-methylpyrrole-4-carboxylic acid methyl ester. Treatment of 2-trichloroacetyl-3-methylpyrrole-4-carboxylic acid methyl ester with sodium methoxide produces 3-methylpyrrole-2,4-dicarboxylic acid methyl ester. N-amination of 3-methylpyrrole-2,4-dicarboxylic acid methyl ester using an aminating reagent such as diphenyl phosphoryl hydroxylamine affords 1-amino-3-methylpyrrole-2,4-dicarboxylic acid methyl ester. Finally, reaction of 1-amino-3-methylpyrrole-2,4-dicarboxylic acid methyl ester with formamide at elevated temperature gives 1,4-dihydro-5-methyl-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (Hunt, J. T.; Bhide, R. S.; Borzilleri, R. M.; Qian, L. WO 00/71129, Nov. 30, 2000). Although a number of 1,4-dihydro-5-substitued-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylates can be prepared by this method, this process is limited due to its lengthy chemical transformations, the use of hazardous aminating reagents and expensive chromatographic separation of products. WO 02/40486 describes an improved synthesis of 3-methylpyrrole-2,4-dicarboxylates by condensing ethaldehyde and isocyanoacetates in the presence of DBU. The synthesis is shorter, however, generation of the side-product, cyanide, is a safety concern. Preparation of 6-ethyl-1,2,4-triazin-5-one by Raney nickel mediated desulfurization of 6-ethyl-1,2,4-triazin-5-one-3-thione has been reported (Taft, W. E.; Shepherd, R. G. J. Med. Chem. (1967), 10, at 883).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH2:18]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:14][C@@H:13]([CH3:16])[CH2:12][N:7]2[C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Reactant: CCCCC1CCNCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(F)cc32)CC1
Yield: 58 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04)_(0.873 g, 2.50 mmol) and 4-Butylpiperidine (0.371 g, 2.63 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF08) (0.53 g, 58%). 1H NMR (CDCl3) δ 7.01 (d, J=10.0 Hz, 1H), 6.92-6.88 (m, 1H), 6.68-6.64 (m, 1H), 5.57 (q, J=32.4 Hz, J=15.2 Hz, 2H), 4.02-3.83 (m, 2H), 2.92-2.70 (m, 2H), 2.23-2.10 (m, 2H), 2.04-1.97 (m, 2H), 1.81 (t, J=10.8 Hz, 1H), 1.72-1.61 (m, 2H), 1.36-1.19 (m, 9H), 0.90-0.88 (m, 6H); 13C NMR (CDCl3) δ 164.8, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.3 Hz), 130.0 (d, J=10.4 Hz), 117.6 (d, J=9.6 Hz), 109.4 (d, J=23.1 Hz), 103.5 (d, J=29.3 Hz), 67.8, 64.1, 56.0, 54.3, 45.7, 36.5, 36.0, 33.0, 32.5, 29.5, 29.2, 23.1, 17.1, 14.3.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31].Cl.[CH3:33][NH:34][CH3:35].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:34]([CH3:35])[CH3:33])=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(-c2cc3cc(CN(C)C)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Yield: 18.1 %

Procedure:
In a similar manner to Step 2 of Example 6, a crude product of 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.713 g) was dissolved in acetonitrile (20 mL), and the solution was treated with dimethylamine hydrochloride (2.75 g, 33.8 mmol), triethylamine (4.70 mL, 33.8 mmol), acetic acid (1.90 mL, 33.8 mmol) and sodium triacetoxyborohydride (1.10 g, 5.07 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=4/1) to obtain 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(dimethylaminomethyl)indol-2-yl]isoindolinone (0.138 g, yield 19%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:29][CH2:30][CH:31]=[C:32]2[C:38]3[CH:39]=[CH:40][CH:41]=[N:42][C:37]=3[CH2:36][O:35][C:34]3[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]2=3)[CH2:13][CH2:12]1
Reactant: COC(=O)c1cc(Cl)ccc1N1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: COC(=O)c1cc(Cl)ccc1N1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-2-piperazin-1-yl-benzoic acid methyl ester (0.23 g, 0.916 mmol) in isopropanol (8.0 mL) was added 2,6-lutidine (0.16 mL, 1.33 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.26 g, 0.67 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% Methanol) to yield the title compound. 1H-NMR (DMSO) δ: 1.40 (6H, s), 2.15–2.55 (8H, m), 2.75–2.95 (4H, m), 3.75 (3H, s), 5.20 (2H, br s), 6.10 (1H, t), 6.65 (1H, dd), 7.00–7.60 (6H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 548 (M+1), UV retention time: 1.56 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[CH3:19])(=[O:3])[CH3:2].[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][O:24]N1C2C(=CC(OC)=CC=2)C=C1.CN(C)CCC[C:42]1[CH:50]=[C:49]2[C:45]([CH2:46][CH2:47][NH:48]2)=[CH:44][C:43]=1[O:51][CH2:52]C>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:48]3[C:49]4[C:45](=[CH:44][C:43]([O:51][CH3:52])=[C:42]([O:24][CH2:23][CH2:22][N:21]([CH3:36])[CH3:20])[CH:50]=4)[CH2:46][CH2:47]3)=[O:17])=[CH:14][CH:15]=2)=[CH:6][C:5]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1C
Reactant: COc1ccc2c(ccn2OCCN(C)C)c1
Reactant: CCOc1cc2c(cc1CCCN(C)C)NCC2
Product: COc1cc2c(cc1OCCN(C)C)N(C(=O)c1ccc(-c3ccc(C(C)=O)c(C)c3)cc1)CC2

Procedure:
The title compound was prepared from 4'-acetyl-3'-methylbiphenyl-4-carboxylic acid (D21) and 2,3-dihydro-6-(2-dimethylaminoethoxy-5-methoxy-1H-indole (D14) using a similar procedure to Example 2 as a yellow solid mp 160°-162° C. (47%).
Reaction SMILES: [CH:1]([N:4]([CH:10]([CH3:12])[CH3:11])[C:5](=[O:9])[O:6][CH2:7]Cl)([CH3:3])[CH3:2].[OH:13][C@@H:14]([C@H:16]1[C:35](=[O:36])[N:18]2[C:19]([C:32]([O-:34])=[O:33])=[C:20]([S:22]/[CH:23]=[CH:24]\[C:25]3[S:29][CH:28]=[N:27][C:26]=3[CH2:30][OH:31])[CH2:21][C@H:17]12)[CH3:15].[Na+].C(OCC)(=O)C>CN(C)C(=O)C.[Cl-].[Na+].O>[OH:13][C@@H:14]([C@H:16]1[C:35](=[O:36])[N:18]2[C:19]([C:32]([O:34][CH2:7][O:6][C:5]([N:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2])=[O:9])=[O:33])=[C:20]([S:22]/[CH:23]=[CH:24]\[C:25]3[S:29][CH:28]=[N:27][C:26]=3[CH2:30][OH:31])[CH2:21][C@H:17]12)[CH3:15]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)C[C@H]12
Reactant: CC(C)N(C(=O)OCCl)C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Temperature: 30 °C
Reaction time: 3.5 h
Yield: 80.2 %

Procedure:
Chloromethyl N,N-diisopropylcarbamate (54 mg) and 75 mg of n-tetrabutyl ammonium bromide were added to 2 ml of a solution of 100 mg of sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-carbapen-2-em-3-carboxylate in N,N-dimethylacetamide, and the mixture was stirred at 30° C. for 3.5 hr. Ethyl acetate (10 ml) and 10 ml of semi-saturated brine were added to the reaction solution, followed by separation. The organic layer was washed three times with 10 ml of semi-saturated brine, was dried over anhydrous magnesium sulfate, and was filtered. Ethyl acetate was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=15:1) to give 108 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[C:19]3=[N:20][C:21](Cl)=[N:22][CH:23]=[C:18]3[CH:17]=[N:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>O1CCOCC1.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([CH3:37])=[C:31]([S:33](=[O:35])(=[O:34])[NH2:36])[CH:32]=4)=[N:22][CH:23]=[C:18]3[CH:17]=[N:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Cn2ncc3cnc(Cl)nc32)CC1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Nc2ncc3cnn(C[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3n2)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A solution of tert-butyl-cis-4-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (1.66 g, 4.53 mmol, prepared using A from Preparation #2 and tert-butyl-cis-(4-hydroxymethyl)cyclohexylcarbamate [AMRI]), 5-amino-2-methylbenzenesulfonamide (1.10 g, 5.89 mmol, Waterstone), and sodium tert-butoxide (1.306 g, 13.59 mmol) in 1,4-dioxane (15 mL) was stirred at ambient temperature for about 30 min. In a separate 10 mL nitrogen purged vial charged with Pd2(dibenzylideneacetone)3 (0.415 g, 0.453 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.789 g, 1.86 mmol) was added 1,4-dioxane (2 mL) followed by heating to about 80° C. for about 2 min. The mixture was subsequently cooled to ambient temperature. The catalyst solution was added to the reaction mixture at ambient temperature and the reaction mixture was heated to about 80° C. for about 16 h. The reaction mixture was cooled to ambient temperature then water (100 mL) and EtOAc (50 mL) were added and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2×50 mL) and the combined organic extracts were dried over anhydrous MgSO4, filtered through a silica gel pad, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 50% EtOAc in heptane to provide tert-butyl-cis-4-((6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.58 g, 25%) as a light yellow solid. LC/MS (Table 2, Method a) Rt=1.38 min; MS m/z: 516 (M+H)+.
Reaction SMILES: [C:1]([N:11]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][O:13][C:12]1=[O:22])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:23]([N:30]([CH2:34][Si](C)(C)C)[CH2:31]OC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:23]([N:30]1[CH2:34][C@@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:2]([C:1]([N:11]2[C@@H:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][O:13][C:12]2=[O:22])=[O:10])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1OC[C@H](c2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Reaction time: 0.33 h

Procedure:
The compound from step 8b (294 mg, 1.2 mmol) was dissolved in toluene (10 mL), and the solution flushed with N2. N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (284 mg, 0.227 mmol) was added, the mixture was stirred for 20 minutes and trifluoroacetic acid (1M, 0.1 mL, 0.10 mmol) was added dropwise. The mixture was stirred for 1.5 hour at room temperature, then diluted with 50 mL of ethyl acetate, washed with 5% aqueous NaHCO3 and dried over Na2SO4. The solvent was removed and the residue was dried under vacuum (542 mg). The isomers were separated by chromatography on silica gel, and the major isomer (3R,4R) was taken to the next step. MS m/z 427 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:26])[CH2:17][C:18]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19].[NH2:27]/[C:28](/[CH3:32])=[CH:29]\[C:30]#[N:31].C(O)(=O)C>CC(O)C>[C:30]([C:29]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]([C:18]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])=[C:16]([CH3:26])[NH:27][C:28]=1[CH3:32])#[N:31]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: C/C(N)=C/C#N
Reactant: CC(=O)CC(=O)OCC(F)(F)F
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)OCC(F)(F)F)=C(C)N1

Procedure:
60 mg (0.32 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 60.1 mg (0.32 mmol) of 2,2,2-trifluoroethyl 3-oxobutanoate, 26.2 mg (0.32 mmol) of 3-aminocrotononitrile and 19.1 mg (0.32 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 4 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 103 mg (77% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br-].[CH3:14][C:15]1[C:16]([Zn+])=[N:17][CH:18]=[CH:19][CH:20]=1>C1COCC1.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>[CH3:14][C:15]1[C:16]([C:2]2[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1cccnc1[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cccnc1-c1cnc(C#N)c([N+](=O)[O-])c1
Yield: 87.8 %

Procedure:
Heat a solution of 5-bromo-3-nitropyridine-2-carbonitrile (228 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg), 3-methyl-2-pyridylzinc bromide (0.5 M in THF, 3 mL, 1.5 mmol) in THF (5 mL) to 60° C. for 2 hours. Cool the solution and partition between ethyl acetate (10 mL) and saturated aqueous NaHCO3 (10 mL). Extract the aqueous solution with ethyl acetate (2×15 mL), wash with water (10 mL), brine (10 mL), dry (MgSO4) and evaporate to obtain the title compound as a pale yellow solid (211 mg, 88%).