Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[N:41]1([S:47]([CH2:50][CH2:51][CH2:52][O:53][C:54]2[CH:55]=[CH:56][C:57]3[C:58]4[N:59]([CH2:65][CH2:66][N:67]=4)[C:60]([NH2:64])=[N:61][C:62]=3[CH:63]=2)(=[O:49])=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C.CCOC(C)=O>[N:41]1([S:47]([CH2:50][CH2:51][CH2:52][O:53][C:54]2[CH:55]=[CH:56][C:57]3[C:58]4[N:59]([CH2:65][CH2:66][N:67]=4)[C:60]([NH:64][C:7]([C:5]4[CH:4]=[N:3][CH:2]=[N:1][CH:6]=4)=[O:9])=[N:61][C:62]=3[CH:63]=2)(=[O:48])=[O:49])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12
Reactant: O=C(O)c1cncnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12)c1cncnc1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To pyrimidine-5-carboxylic acid (95.0 mg, 0.77 mmol) in DMF (1 ml) was added HATU (342 mg, 0.9 mmol) and 4-methylmorpholine (91 mg, 0.9 mmol). The mixture was stirred for 5 min then 8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 1, 250 mg, 0.64 mmol) in DMF (2 mL) was added. The resulting solution was allowed to stir at rt for 16 h. It was diluted with EtOAc and filtered rinsing with EtOAc and MeOH to give the title compound (195 mg, 61%). TLC Rf=0.68 in 10% MeOH/CH2Cl2, HPLC MS RT=1.13 min, MH+=500.4; 1H NMR (DMSO-d6) δ: 2.25 (2H, m), 3.21 (4H, m), 3.30 (2H, m), 3.67 (4H, m), 4.23 (2H, t), 4.31 (2H, t), 4.60 (2H, t), 7.25 (1H, d), 7.78 (1H, s), 8.16 (1H, d), 9.44 (1H, s), 9.50 (2H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]3)=[CH:20][CH:19]=2)=[O:16])=[CH:11][CH:10]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]3)=[CH:20][CH:19]=2)=[O:16])=[CH:11][CH:10]=1)#[N:2]
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4ccccc4C#N)nc3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4ccccc4C#N)nc3)cc2)CCN1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[{[6-(2-cyanophenyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D49) (0.091 g, 0.173 mmol) was stirred in DCM (10 mL) and TFA (2.5 mL) was added drop-wise. The reaction mixture was stirred for ˜1 h, then concentrated in vacuo and re-diluted with DCM and water. The separated aqueous layer was basified to pH14 with concentrated NaOH solution, then extracted with DCM which was dried (Na2SO4) and concentrated to give the crude product which was purified by column chromatography. Elution with 0-10% MeOH/DCM yielded the title compound as a colourless oil (0.054 g). δH (CDCl3, 400 MHz) 8.59 (1H, s), 7.83 (1H, dd), 7.78 (2H, m), 7.67 (1H, m), 7.50 (1H, m), 7.23 (2H, d), 7.05 (2H, d), 3.54 (3H, s), 3.45 (2H, s), 2.89-3.02 (3H, m), 2.71 (2H, m), 2.09 (1H, t), 1.79 (1H, t), 1.75 (br.s) 1.07 (3H, d). MS (ES): MH+ 426.2.
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(OC([N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43]Cl)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>C(#N)C.[I-].[K+]>[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43][N:11]([C@H:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCN[C@@H]1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2ccccc2[nH]1)[C@@H]1CCCc2cccnc21
Temperature: 50 °C
Reaction time: 22 h
Yield: 111.7 %

Procedure:
To a solution of 2-{4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amino]-butyl}-isoindole-1,3-dione (135.3 g, 0.39 mol) and 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (103 g, 0.39 mol) in acetonitrile (780 mL) at room temperature was added diisopropylethylamine (101 mL, 0.58 mol) and potassium iodide (6.4 g, 0.04 mol) and the mixture heated to 50° C. for 3 hours. The mixture was then concentrated under reduced pressure and redissolved in methyl t-butyl ether (500 mL) and water (500 mL). The pH was adjusted to 2 with 6N HCl then the phases were separated. The aqueous layer was washed with methyl t-butyl ether (500 mL). The aqueous phase was stirred for 22 hours, adding 6N HCl as needed to maintain pH=2. The solution was basified to pH 10-11 with 10N NaOH and extracted with toluene (2×1.5 L). The organic phase was washed with 1N NaOH (1×200 mL) and brine (1×200 mL). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 2-{4-[(R)-(1H-benzimidazol-2-ylmethyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-isoindole-1,3-dione (209 g). 1H NMR (300 MHz, CDCl3, δ ppm) 0.75-1.75 (series of m, 5H), 1.80-2.10 (2m, 2H), 2.15-2.25 (m, 1H), 2.55-2.90 (m, 4H), 3.52 (t, 2H, J=7.0 Hz), 3.95-4.10 (m, 1H), 4.01 (d, 1H, J=17.0 Hz), 4.11 (d, 1H, J=17.0 Hz), 7.10-7.30 (m, 4H), 7.39 (d, 1H, J=7.5 Hz), 7.50-7.55 (m, 1H), 7.60-7.70 (m, 2H), 7.70-7.80 (m, 2H), 8.60 (d, 1H, J=3.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([CH3:15])[N:12]=[C:13](Br)[C:8]2=[N:7][C:6]=1[CH2:16][CH3:17])=[O:4].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([CH3:15])[N:12]=[C:13]([C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=3[Cl:25])[C:8]2=[N:7][C:6]=1[CH2:16][CH3:17])=[O:4]
Reactant: CCc1nc2c(Br)nc(C)cn2c1C(=O)OC
Reactant: OB(O)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1nc2c(-c3ccc(Cl)cc3Cl)nc(C)cn2c1C(=O)OC
Yield: 107.4 %

Procedure:
8-Bromo-2-ethyl-6-methylimidazo[1,2-a]pyrazine-3-carboxylic acid methyl ester (0.30 g, 1.0 mmol) was dissolved in a mixed solvent of toluene (5.6 mL) and methanol (1.4 mL). Then 2,4-dichlorobenzeneboronic acid (0.382 g, 2.0 mmol) and tetrakistriphenylphosphine palladium complex (116 mg, 0.1 mmol) were added thereto, and the mixture was heated under reflux for 4 hours under nitrogen atmosphere. After the reaction mixture was allowed to cool, the solvent was removed. Then the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give the title compound (391 mg) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]1[CH2:21][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClCCl.Br.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]1[CH2:21][C:11]2[N:12]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: BrCc1ccccn1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1Cc2c(n(Cc3ccccn3)c3ccc(C#N)cc23)C1
Reaction time: 21 h
Yield: 85.8 %

Procedure:
Equip a 20 L bottom outlet flask with overhead agitation, thermocouple, and nitrogen inlet. Charge the flask with (±)-(7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid tert-butyl ester (500 g, 1.68 moles) and dichloromethane (5 L). Begin agitation and add tetra n-butylammonium hydrogen sulfate (58.9 g, 0.168 mol) followed by 2-(bromomethyl)pyridine hydrobromide (510.4 g, 2.02 moles). Add deionized water (2 L) followed by a 50% NaOH solution (445.3 mL, 8.41 moles). Stir the resulting mixture vigorously overnight (about 21 h). Stop the agitation, allow the layers to separate, and discard the aqueous (upper) layer. Wash the organics with deionized water (3×4 L), dry over sodium sulfate, and concentrate in vacuo to about 500 mL. Purify the crude material over a silica gel plug (7 Kg Keiselgel 60) using 1:1 ethyl acetate/heptane as eluent. Concentrate the eluent in vacuo to afford 560 grams of the titled compound as an off-white solid (81.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[C:13]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:14][CH:15]=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH:44]1[CH2:47][CH2:46][CH2:45]1>>[N:44]1([C:2]2[CH:7]=[C:6]([C:8]3[C:12]4[C:13]([O:17][CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[N:14][CH:15]=[CH:16][C:11]=4[NH:10][N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:47][CH2:46][CH2:45]1
Reactant: Clc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)ccn1
Reactant: C1CNC1
Agent: Cl
Product: c1cc(-c2n[nH]c3ccnc(OC4CCOCC4)c23)cc(N2CCC2)n1
Yield: 22 %

Procedure:
Prepared according to the procedure described in Example 111, by reacting 3-(2-chloropyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine with azetidine hydrochloride to give the title compound (11.3 mg, 22% over two steps). LC-MS (Method G): m/z=352.1 [M+H]+; 3.24 min. 1H-NMR (400 MHz, DMSO): δ 13.72 (s, 1H), 8.17-8.11 (m, 1H), 7.91 (d, J=5.6, 1H), 7.29-7.22 (m, 1H), 7.17 (d, J=5.6, 1H), 6.93 (s, 1H), 5.56-5.46 (m, 1H), 4.09-3.95 (m, 4H), 3.85-3.75 (m, 2H), 3.58-3.48 (m, 2H), 2.41-2.31 (m, 2H), 2.11-2.01 (m, 2H), 1.77-1.63 (m, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1.[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>O1CCCC1>[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][C:13]1([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:15][CH2:16][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12]1
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2F)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
In a flask, lithium bis(trimethylsilyl)amide (LHMDS) (9.24 mL of 1.0 M solution in THF, 9.24 mmol) was added to tetrahydrofuran (20 mL). The reaction mixture was cooled to −78° C., and then a solution of 1-tert-butyl 3-methyl piperidine-1,3-dicarboxylate (1.5 g, 6.17 mmol) in tetrahydrofuran (5 mL) was added drop-wise to the reaction mixture at −78° C. The reaction was stirred at −78° C. for 30 minutes. Afterwards, 2-fluorobenzylbromide (1.12 mL, 9.24 mmol) was added, and the reaction was stirred for an additional 3 hours at 0° C. Upon reaction completion, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried with sodium sulfate, and concentrated to yield crude product. The crude product was purified using flash chromatography (0-60% ethyl acetate in hexane) to give the titled compound (1.41 g).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:21])[CH:10]=[C:11]([O:19][CH3:20])[C:12]2=[O:18].[N-:22]=[N+]=[N-].[Na+]>CO>[CH3:6][C:7]1[C:8]2[C:9](=[O:21])[CH:10]=[C:11]([O:19][CH3:20])[C:12](=[O:18])[NH:22][C:13]=2[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=CC(=O)c2c(C)cc(C)cc2C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(=O)c2c(C)cc(C)cc2[nH]c1=O
Yield: 93.4 %

Procedure:
To stirred, ice bath cold, coned H2SO4 (14 mL, Baker), there was added 5,7-dimethyl-2-methoxynaphthalene-1,4-dione (1.00 g, 4.63 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (601 mg, 9.24 mmol, Aldrich) was added in portions over one min. The ice bath was removed and the reaction was allowed to stir at rt for 18 h under N2. Nitrogen evolution was noted. The reaction was added to crushed ice (100 mL) to give a brown suspension. A solution of 30% MeOH/70% CHCl3 (90 mL) was added and vigorously stirred until all the solid had dissolved. The layers were separated and the aqueous portion was extracted with 30% MeOH/70% CHCl3 (2×30 mL). The combined red organic portion was washed with water (1×30 mL), saturated NaHCO3 (1×30 mL) and brine (1×30 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (~1 g). Crystallization from 95% EtOH (dissolved in 40 mL, hot filtered, concd to 25 mL, allowed to cool to rt then in an ice bath) a gave colorless fluffy needles (678 mg, 63%, pure by 1H NMR); mp 237°-238° C.; 1H NMR (DMSO-d6) δ2.25 (s, 3H), 2.29 (s, 3H), 3.70 (s, 3H), 6.28 (s, 1H), 6.90 (s, 1H), 6.94 (s, 1H), 10.94 (s, 1H); 13C NMR (DMSO-d6) δ20.66, 56.04, 113.58, 118.69, 127.47, 128.10, 135.44, 137.45, 141.20, 153.83, 160.10, 190.53; IR (KBr) 3207 (m), 3003 (m), 2920 (m), 1682 (s), 1645 (s), 1619 (s), 1241 (m), 1224 (m), 855 (m); MS (m/z) 231 (M+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4](Br)[CH:3]=1.[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:15][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:2]1[CH:7]=[C:6]([C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15])[CH:5]=[C:4]([C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15])[CH:3]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCC#Cc1cc(C#CCCCO)cc(C#CCCCO)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.9 %

Procedure:
1,3,5-Tribromobenzene (10 g, 31.76 mmol), 4-pentyn-1-ol (10.69 g, 127.06 mmol) and bis(triphenylphosphine)palladium(II) dichloride were stirred in triethylamine under nitrogen for 5 minutes. Copper(I) iodide (92 mg, 0.48 mmol) was added and the mixture was stirred for 6 hours at 80° C. The mixture was cooled to room temperature, filtered through a celite pad and rinsed with ethyl acetate. The combined filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (CHCl3:MeOH 10:1) to afford 7.61 g of 1,3,5-tris-(5-hydroxy-1-pentynyl)benzene. Yield: 74%. 1H NMR (300 MHz, CDCl3) δ 7.31 (3, 3 h), 3.81 (t, J=6.0 Hz, 6H), 2.52 (t, J=6.9 Hz, 6H), 1.85 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 133.8, 124.2, 90.5, 80.0, 61.9, 31.5, 16.2 ppm.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:21](I)[CH3:22].O>CS(C)=O.C1COCC1>[CH3:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:21][CH3:22])[C:8]#[N:9]
Reactant: CCI
Reactant: CC(C#N)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5 g (38 mmol) of 2-phenylpropionitrile in 50 mL of DMSO was added 42 mL of a 1M solution of NaHMDS in THF. After 15 minutes, the reaction was cooled to 0° C. and 4.6 mL of ethyl iodide was added. The reaction was monitored by TLC. After 30 minutes, the mixture was poured into water and extracted with diethyl ether. The combined organics were washed with four portions of water, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6.1 g of 2-methyl-2-phenylbutyronitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[C:10]=1[N+:21]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:20])[CH:17]([CH3:18])[CH3:19])[C:10]=1[NH2:21]
Reactant: CC(C)C(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CC(C)C(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1N
Yield: 75 %

Procedure:
[4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1,2-dimethyl-propyl)-amine (0.26 g, 0.74 mmol) and Na2S2O4 (1.03 g, 5.94 mmol) were treated substantially as described in Part E of Example 9 to yield 0.18 g (75%) of crude 4-(2,4-dichloro-phenyl)-N2-(1,2-dimethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 324.3 [(M+H)+, 70].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][O:58][CH:59]1[CH2:64][CH2:63][CH2:62][N:61]([CH2:65][C:66]2[CH:71]=[CH:70][C:69]([CH2:72][NH:73][CH3:74])=[CH:68][CH:67]=2)[CH2:60]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:73]([CH2:72][C:69]3[CH:68]=[CH:67][C:66]([CH2:65][N:61]4[CH2:62][CH2:63][CH2:64][CH:59]([O:58][CH3:57])[CH2:60]4)=[CH:71][CH:70]=3)[CH3:74])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.11 mmol), EDCI (30 mg, 0.16 mmol), HOBt (23 mg, 0.17 mmol), DIPEA (0.04 mL, 0.22 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (39 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 6-fluoro-1H-indazole (6.46 mmol, 880 mg) in DMF (15 mL) cooled to 0° C. under Ar was added 95% NaH (6.46 mmol, 163 mg). The resulting mixture was stirred for 15 minutes before tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (7.11 mmol, 2.52 g) was added. After an additional 15 minutes at 0° C., the ice bath was removed and the reaction vessel placed in a 110° C. bath for 2.75 hours. After cooling to ambient temperature, the DMF was removed in vacuo and ethyl acetate (100 mL) was added. The organic layer was washed with water and brine, dried (MgSO4), filtered and the solvent removed in vacuo. The resulting residue was purified by SiO2 column chromatography (0-40% EtOAc/hexanes) to yield tert-butyl 4-(6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:9](Cl)=[O:10].[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:9]([NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:21]1)=[O:10]
Reactant: O=C(Cl)C(c1ccccc1F)c1ccccc1F
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C(c1ccccc1F)c1ccccc1F
Yield: 32.8 %

Procedure:
2,2-Bis(2-fluorophenyl)acetyl chloride (0.74 g) and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.42 g) were reacted under the same conditions as in Example 53 to give (S)-2,2-bis(2-fluorophenyl)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)acetamide (0.29 g), melting point 107-108° C.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[N:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].CC1C=CC=C(C)N=1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[CH2:46]([O:45][C:43]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[N:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:14]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:44])[CH3:47]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(-c3ccccc3)c2C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(-c3ccccc3)c(C)c2Cc2ccc(OC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1-phenyl-1H-pyrazole (0.18 g) and 2,6-dimethylpyridine (0.069 mL) in acetonitrile (5 mL) was added ethyl chloroformate (0.045 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=15/1) to give the title compound (0.13 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][N:8]=1.[CH3:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24](=O)[O:25]N2C(=O)CCC2=O)=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24]([N:14]2[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:4]3[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[O:25])=[CH:20][CH:19]=1
Reactant: COc1nccnc1NCC1CCNCC1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nccnc1NCC1CCN(C(=O)OCc2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 127, STEP 3) (0.093 g, 0.00042 mol) and N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A) (118 mg) in DMF (2 mL) was stirred at rt for 18 h. The reaction was diluted with ethyl acetate (30 mL), washed with 10% aqueous sodium bicarbonate (20 mL) followed by brine (10 mL), concentrated in vacuo and chromatographed on silica using a gradient elution of 5–15% acetone/dichloromethane. Concentration in vacuo followed by crystallization from ether/hexane gave the title compound. M.S. (M+1): 371.