Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)=O)C.[NH2:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[F:14][C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:15][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH3:24])[N:16]=2)[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(C(=O)c1ccc(F)c(F)c1)N(C)C
Product: CCOC(=O)c1ccc(-c2ccc(F)c(F)c2)nc1C

Procedure:
The title compound was prepared from dimethylamino-(3,4-difluorophenyl)-propan-1-one and ethyl 3-aminocrotonate using the general procedure outlined in D18. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.26 (d, 1H), 7.96 (ddd, 1H), 7.79 (m, 1H), 7.57 (d, 1H), 7.20-7.31 (m, 1H), 4.40 (q, 2H), 2.90 (s, 3H), 1.42 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([OH:10])=[O:9])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[NH:3]1.OS(O)(=O)=O.O=S(Cl)Cl.[CH2:28](O)[CH3:29]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]([O:10][CH2:28][CH3:29])=[O:9])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[NH:3]1
Reactant: O=C(O)c1[nH]c(=O)[nH]c(=O)c1Oc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1[nH]c(=O)[nH]c(=O)c1Oc1ccccc1

Procedure:
The required starting compound may also be prepared as follows: 1.8 g of 2,6-dioxo-5-phenoxy-1,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid (preparation described in: Khim Geterotsikl. Soedin., 1974, p1527) are emulsified in 65 ml of ethanol, 0.92 ml of conc. H2SO4 and 0.92 ml of SOCl2 are subsequently added and the mixture is heated at reflux for 12 hrs. Subsequently, the mixture is concentrated on a rotary evaporator and the seperated solid is filtered off under suction and chromatographed on silica gel (eluent: CH2Cl2 /ether: 3/1). There are obtained 520 mg of ethyl 2,6-dioxo-5-phenoxy-1,2,3,6-tetrahydro-pyrimidine-4-carboxylate as a solid. MS: M=276.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccccc2c1)n1cc(C2CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), 2-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:61][O:62][C:63]1[CH:70]=[C:69]([O:71][CH3:72])[CH:68]=[CH:67][C:64]=1[CH2:65][NH2:66]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:61][O:62][C:63]1[CH:70]=[C:69]([O:71][CH3:72])[CH:68]=[CH:67][C:64]=1[CH2:65][NH:66][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1cc(C(C)(C)O)cc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CNc2cc(C(C)(C)O)cc(C)n2)c(OC)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A flask containing a mixture of 2-(2-chloro-6-methylpyridin-4-yl)propan-2-ol (303 mg, 1.63 mmol), tris(dibenzylideneacetone)dipalladium(0) (149 mg, 0.163 mmol), Xantphos (189 mg, 0.326 mmol), and cesium carbonate (798 mg, 2.45 mmol) was purged with argon for 5 minutes. To this mixture was added 2,4-dimethoxybenzylamine (0.983 mL, 6.53 mmol) and 1,4-dioxane (7 mL). The reaction mixture was purged with argon for 5 minutes, and then heated to 100° C. After 4 hours, the reaction mixture was cooled, diluted with ethyl acetate (50 mL), filtered through CELITE, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-60% ethyl acetate/hexanes, linear gradient) to afford 2-{2-[(2,4-dimethoxybenzyl)amino]-6-methylpyridin-4-yl}propan-2-ol. MS ESI calc'd. for C18H25N2O3 [M+H]+ 317. found 317. 1H NMR (500 MHz, DMSO-d6) δ 7.12 (d, J=8.5 Hz, 1H), 6.51 (d, J=2.5 Hz, 1H), 6.44-6.40 (m, 2H), 6.38 (d, J=7.0 Hz, 2H), 4.90 (s, 1H), 4.30 (d, J=5.5 Hz, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 2.19 (s, 3H), 1.29 (s, 6H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6](C(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[H-].[Na+].[Cl:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.C(OCC)C>C1COCC1.C(Cl)Cl.CCO>[Cl:24][C:25]1[N:30]=[CH:29][C:28](/[CH:31]=[C:3](/[C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[NH:6][CH:5]=2)\[C:1]#[N:2])=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: COc1ccc2c(c1)c(CC#N)cn2C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3ccc(Cl)nc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-5-methoxy-1H-indol-1-carboxylate (4.9 g, 17 mmol, 1.0 eq.) in anhydrous THF (400 mL) was added, under an argon atmosphere, NaH (930 mg, 80%, 31 mmol, 1.8 eq.). The mixture was stirred at room temperature for 10 minutes, and then cooled to 0° C. before the addition of 6-chloro-pyridine-3-carbaldehyde (3 g, 21 mmol, 1.2 eq.). The reaction apparatus was protected from light and the mixture was stirred at room temperature for 1 hour, and then quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 99/1) to afford, after trituration with diethyl ether, the compound (49) as a yellow powder (3.8 g, 72%). TLC: Rf=0.40 (CH2Cl2/EtOH, 96/4); mp: 184° C.; IR νmax (cm−1): 2208 (νCN); 1H NMR (DMSO, 300 MHz) δ (ppm): 3.83 (3H, s, 5′-methoxy), 6.90 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.40 (1H, d, J7′-6′=8.9 Hz, H7′), 7.49 (1H, d, J4′-6′=2.4 Hz, H4′), 7.67 (1H, d, J5″-4″=8.5 Hz, H5″), 7.73 (1H, s, H3), 7.79 (1H, s, H2′), 8.37 (1H, dd, J4″-5″=8.5 Hz, J4″-2″=2.4 Hz, H4″), 8.81 (1H, d, J2″-4″=2.4 Hz, H2″), 11.70 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 55.6 (5′-methoxy), 102.0 (C4′), 108.2 (C2), 110.1 (C3′), 112.4 (C6′), 113.2 (C7′), 117.8 (C1), 123.9 (C3a′), 124.2 (C5″), 128.0 (C2′), 130.3 (C3), 130.4 (C3″), 132.3 (C7a′), 137.9 (C4″), 149.8 (C6″), 150.2 (C2″), 154.6 (C5′); ESI-MS: 310.1 ([M+H]+), 334.1 ([M+Na]+); HRESI-MS: m/z 310.0733 (calcd for C17H13N3O35Cl+, 310.0747).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([C:9]1[CH:10]=[N:11][C:12]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][OH:26])[CH2:20][CH2:19]2)=[CH:13][C:14]=1[CH2:15][CH2:16][CH3:17])([OH:8])[C:4]([F:7])([F:6])[F:5].N1C=CC=CC=1.[C:35](O)(=[O:37])[CH3:36].CO>ClCCl>[C:35]([O:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:12]2[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:27])([F:1])[F:28])=[CH:10][N:11]=2)[CH2:19][CH2:20]1)(=[O:37])[CH3:36]
Reactant: CCCc1cc(N2CCN(CCO)CC2)ncc1C(O)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)O
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1cc(N2CCN(CCOC(C)=O)CC2)ncc1C(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-4-propylpyridin-3-yl}propan-2-ol (208 mg, 0.501 mol) was dissolved in dichloromethane (2.5 mL), added pyridine (121 μL, 1.50 mmol) and anhydrous acetic acid (142 μL, 1.50 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 3 hours. The reaction solution was added methanol, stirred at room temperature for 0.5 hours. The reaction solution was concentrated in vacuo, extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The title compound (247 mg) was obtained as a red-brown oil.
Reaction SMILES: [NH:1]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@@H:2]([C:14]([N:16]([CH3:49])[C@H:17]([C:35]([NH:37][CH2:38][C:39]([O:41]CC1C=CC=CC=1)=[O:40])=[O:36])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:34])[NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].C(OCC)C>CO>[NH:1]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@@H:2]([C:14]([N:16]([CH3:49])[C@H:17]([C:35]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:34])[NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:25])=[O:26])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]([F:12])([F:11])[F:13])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)OCc2ccccc2)N(C)C(=O)[C@@H](CCCCNC(=O)C(F)(F)F)NC(=O)OC(C)(C)C)cc1
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)O)N(C)C(=O)[C@@H](CCCCNC(=O)C(F)(F)F)NC(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A solution of Boc-D-Lys(Tfa)-NMeArg(Tos)-Gly-OBzl (11.00 g, 13.5 mmol) in methanol (200 ml) was placed in a Parr shaker bottle, purged with N2 for 10 minutes, and treated with 10% palladium on carbon catalyst (10% Pd/C, 3.6 g). The shaker bottle was further purged with 7 pressurization-evacuation cycles, repressurized, and allowed to shake 90 minutes, during which time the calculated amount of hydrogen was consumed. The catalyst was removed by filtration through a bed of Celite and the filtrate was concentrated under reduced pressure yielding a solid. Trituration with refluxing ethyl ether (75 ml) gave pure product (9.18 g, 94%) as a colorless solid. DCI-MS: [M+H]=724.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:15]N1C(=O)CCC1=O>ClCCl>[Br:15][C:7]1[CH:8]=[C:9]([O:10][C:11]([F:12])([F:13])[F:14])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(OC(F)(F)F)c1O
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(OC(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
2-hydroxy-3-trifluoromethoxybenzaldehyde (10.38 g) was dissolved in dichloromethane (100 mL), and N-bromosuccinimide (9.41 g) was added to the solution, and then the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 10% sodium thiosulfate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (14.27 g) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[O:4][NH2:5].[CH2:11]([N:14]=[C:15]=[O:16])[CH:12]=[CH2:13]>C1(C)C=CC=CC=1>[CH2:11]([NH:14][C:15]([NH:5][O:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[Cl:1])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN=C=O
Reactant: NOc1cc(Cl)ccc1Cl
Solvent: Cc1ccccc1
Product: C=CCNC(=O)NOc1cc(Cl)ccc1Cl
Reaction time: 12 h
Yield: 50.6 %

Procedure:
5.34 g (30.0 mmoles) of 2,5-dichlorophenoxyamine was dissolved in 50 ml of toluene, and then 2.74 g (33.0 mmoles) of allyl isocyanate was added. The mixture was stirred at a temperature of from 25° to 30° C. for 12 hours. The crystals precipitated in the reaction solution were collected by filtration and washed with hexane, whereby, 3.96 g of the desired product was obtained as light yellow crystals (yield: 51%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:12][C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a precooled (0° C.) solution of 5-methoxy-2-methyl-1H-indole (5.0 g, 31.0 mmol) in 100 mL DCM is added BBr3 (1 M solution, 46.5 mL) under a dry nitrogen atmosphere. The solution is then allowed to slowly warm to room temperature over a 2 h period. The solution is then poured into water, neutralized to pH 7 with sat aq sodium bicarbonate solution and extracted with EtOAc. The extract is washed by brine, dried over sodium sulfate, and concentrated to give 2-methyl-1H-indol-5-ol. MS (ESI) m/z 148.2 (M+1).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[OH:11][N:12]([CH:13]([CH2:23][S:24]([N:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:31][CH2:32]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:18]=[CH:19][CH:20]=[CH:21][N:22]=1)[CH:1]=[O:3]
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.9 %

Procedure:
To formic acid (0.36 mL, 9.5 mmol) at 0° C. was added acetic anhydride (90 μL, 0.95 mmol) and the mixture was stirred at RT for 10 minutes. The reaction was then recooled to 0° C., and added to a solution of 2-(4-(hydroxyamino)-5-{[4-(5-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridin-2-yl)piperazin-1-yl]sulfonyl}pentyl)pyrimidine (403 mg, 0.79 mmol) and formic acid (0.36 mL, 9.5 mmol) in THF (3 mL) at 0° C. The reaction was brought to RT and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for one hour. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the title compound as a pale yellow foam (66 mg, 0.11 mmol, 58%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:14]O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.N>[Zn].C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: ON=C(c1ccccn1)c1ccccn1
Agent: N
Agent: [Zn]
Solvent: CCO
Product: NC(c1ccccn1)c1ccccn1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To pyridyl ketone oxim (3 g, 15.1 mmol) was added ethanol (15 ml), concentrated ammonia solution (15 mL) and NH4OAc (1.21 g, 15.8 mmol). The solution was warmed until reflux. To this solution was added 4.64 g Zn in small portions. After the addition of all Zn, the mixture was refluxed for 1 hour and allowed to cool to ambient temperature. The solution was filtered and water (15 ml) was added. Solid NaOH was added until pH>>10 and the solution was extracted with CH2Cl2 (3×20 ml). The organic layers were dried over Na2SO4 and evaporated until dryness. Bis(pyridin-2-yl)methylamine (2.39 g, 12.9 mmol) was obtained as a colourless oil in 86% yield, showing the following analytical characteristics:
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCCCC2)cc1

Procedure:
4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h with piperdine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((piperidin-1-yl)methyl)benzamide. MS (Q1) 406.4 (M)+.
Reaction SMILES: C(O[C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:5])C.[H-].[Na+].[C:13](#[N:15])[CH3:14].CO>C1(C)C=CC=CC=1>[O:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]([CH2:14][C:13]#[N:15])=[O:5]
Reactant: CCOC(=O)c1ccco1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#CCC(=O)c1ccco1
Yield: 75.9 %

Procedure:
63.05 grams (0.5 mole) of furan-2-carboxylic acid ethyl ester and 30.0 grams (1 mole) of sodium hydride (80 weight % suspension in white oil) were reacted with 41 grams (1 mole) of acetonitrile in 500 ml of toluene with the addition of 1 ml of methanol at 90° C. After 3 hours reaction time the toluene was distilled off, the residue stirred with 500 ml of water, acidified with hydrochloric acid to pH 1.5 and the precipitated product filtered off with suction and recrystallized from methanol. There were obtained 51.3 grams (76% of theory) of 2-furanoylacetonitrile having a melting point of 74°-75° C.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:16][CH2:17][CH2:18][CH3:19])([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20].[C:23]([O:27][C:28](=[O:41])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([S:37](=[O:40])(=[O:39])[NH2:38])[CH:31]=1)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH2:16]([C:12]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:3]2[NH:36][C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:28](=[O:41])[O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:31][C:32]=3[S:37](=[O:39])(=[O:40])[N:38]=2)[C:13]1=[O:14])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC1(C)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: Cc1ccccc1
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A solution of Example 27F (0.296 g, 0.885 mmol) and (4-amino-3-sulfamoyl-phenyl)-carbamic acid tert-butyl ester (0.280 g, 0.973 mmol) in toluene (40 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the title compound (0.430 g, 92%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.53 (m, 1 H) 0.69 (m, 3 H) 0.87 (m, 1 H) 1.08 (m, 2 H) 1.46 (m, 9 H) 1.55 (m, 3 H) 2.01 (m, 1 H) 2.20 (m, 1 H) 7.60 (m, 5 H) 8.13 (m, 2 H) 9.83 (m, 1 H) 13.93 (m, 1 H). MS (ESI−) m/z 524 (M−H)−.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH:26]=O)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=[N:36]2)[CH2:31][CH2:30]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCN(CC)CC>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH2:26][N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[N:36]4)[CH2:33][CH2:34]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3]
Reactant: c1ccc2c(c1)nnn2C1CCNCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(n3nnc4ccccc43)CC2)C1
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.084 g, 0.21 mmol) in CH2Cl2 (0.5 mL) were added 1-piperidin-4-yl-1H-benzotriazole hydrochloride (Maybridge Chemicals, 0.050 g, 0.21 mmol), Et3N (0.1 mL) and glacial AcOH (12 L, 0.21 mmol) in that order and stirred for 20 min. NaBH(OAc)3 (0.058 g, 0.27 mmol) was added and stirred under nitrogen overnight. Saturated NaHCO3 (1 mL) was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 mL). The combined organic extracts were washed with brine (3 mL), dried over Na2SO4, and removed under reduced pressure. MPLC of the crude afforded the desired compound as a white solid (0.098 g, 80%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0.44. MS (electrospray): exact mass calculated for C28H32F3N7O2S, 587.23. m/z found 588.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.00 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.41 (dt, J=0.9, 7.6 Hz, 1H), 7.30 (dt, J=0.9, 7.6 Hz, 1H), 4.59 (br t, J=11.2 Hz, 1H), 4.50 (s, 2H), 4.10 (t, J=6.7 Hz, 2H), 3.63 (t, J=5.8 Hz, 2H), 3.00 (br d, J=12.0 Hz, 2H), 2.89 (t, J=5.8 Hz, 2H), 2.86 (s, 3H), 2.38-2.27 (m, 4H), 2.17-1.99 (m, 6H).
Reaction SMILES: NC1C=C([C@H](NC(N2C(=O)[C@@H](CC3C=C(Cl)C=CC=3OC)CN3C(C)=NN=C3C2)=O)CC)C=CC=1C(OC(C)(C)C)=O.[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([O:82][CH3:83])=[C:48]([CH:81]=1)[CH2:49][C@H:50]1[CH2:56][N:55]2[C:57]([OH:60])=[N:58][N:59]=[C:54]2[CH2:53][N:52]([C:61]([NH:63][C@@H:64]([C:67]2[CH:68]=[C:69]([CH:77]=[CH:78][CH:79]=2)[C:70]([O:72]C(C)(C)C)=[O:71])[CH2:65][CH3:66])=[O:62])[C:51]1=[O:80]>>[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([O:82][CH3:83])=[C:48]([CH:81]=1)[CH2:49][C@H:50]1[CH2:56][N:55]2[C:57]([OH:60])=[N:58][N:59]=[C:54]2[CH2:53][N:52]([C:61]([NH:63][C@@H:64]([C:67]2[CH:68]=[C:69]([CH:77]=[CH:78][CH:79]=2)[C:70]([OH:72])=[O:71])[CH2:65][CH3:66])=[O:62])[C:51]1=[O:80]
Reactant: CC[C@@H](NC(=O)N1Cc2nnc(O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1cccc(C(=O)OC(C)(C)C)c1
Agent: CC[C@@H](NC(=O)N1Cc2nnc(C)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c(N)c1
Product: CC[C@@H](NC(=O)N1Cc2nnc(O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1cccc(C(=O)O)c1

Procedure:
Instead of the starting material of Example 87, Step (3), that is, the compound 87b, the compound 92a was used for a similar procedure as in Example 87, Step (3) to obtain the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1>CS(C)=O.C(OCC)(=O)C>[NH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:29]2[CH2:30][CH2:31][N:26]([CH2:12][CH:13]3[O:25][C:17]4=[C:18]5[C:22](=[CH:23][CH:24]=[C:16]4[O:15][CH2:14]3)[NH:21][CH:20]=[CH:19]5)[CH2:27][CH:28]=2)=[CH:33]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]ccc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4[nH]ccc4c3O2)C1

Procedure:
A solution of 0.65 g (1.8 mmole) of (2R)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl 4-methylbenzenesulfonate and 0.71 g (3.6 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl )-1H-indole in 30 mL of DMSO was heated at 65° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 2-4% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with methylene chloride/hexane (1:1) to give 0.39 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 126° C., which retains one equivalent of DMSO.