Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=NNC(N)=S)=[CH:4][CH:3]=1.C[OH:18].NNC(N)=S>CC(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: NC(=S)NN=C1CCCc2ccc(Br)cc21
Reactant: CO
Agent: NNC(N)=S
Solvent: CC(=O)O
Product: O=C1CCCc2ccc(Br)cc21
Yield: 68 %

Procedure:
7-Bromo-1-tetralone thiosemicarbazone (21) Into a round bottom flask containing the appropriate ketone (0.347 g, 1.54 mmol), 10 mL of anhydrous methanol were added and the solution was refluxed for about 10 minutes. To the warm ketone solution, thiosemicarbazide (0.246 g, 2.70 mmol) and 0.7 mL of 1% solution of HOAc were added. The reaction mixture was refluxed under nitrogen atmosphere for 18 h, at which point, the solvent was evaporated. The crude reaction mixture was purified by flash chromatography (30% EtOAc/70% hex) which afforded 0.314 g (1.05 mmol) of the product in a 68% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:7]2=[O:12].C(Cl)(Cl)(Cl)[Cl:21].ClN1C(=O)CCC1=O.CN(C)C=O>ClCCl>[C:16]([O:15][CH2:14][C@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:21])[C:2]=2[NH2:1])[C:7]1=[O:12])[CH3:19])(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)cccc2c1=O
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of acetic acid (R)-2-(5-amino-1-oxo-1H-isoquinolin-2-yl)-propyl ester (20 g, 0.07 mol) in carbon tetrachloride (400 mL, 4 mol) at 60° C. was added a solution of N-chlorosuccinimide (11 g, 0.082 mol) in N,N-dimethylformamide (140 mL, 1.8 mol) in 50 minutes. The mixture was stirred at 60° C. for an additional 15 minutes. The cooled mixture was diluted with dichloromethane (400 mL), washed with sodium bicarbonate (100 mL×3), and concentrated under reduced pressure. The mixture was purified by flash chromatography to afford the desired product as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl.[NH2:12][C@@H:13]1[C@@H:18]2[CH2:19][C@@H:15]([CH2:16][CH2:17]2)[C@@H:14]1[CH2:20][OH:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([NH:12][C@H:13]2[C@@H:14]([CH2:20][OH:21])[C@H:15]3[CH2:19][C@@H:18]2[CH2:17][CH2:16]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(N)cc1N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 280 mg, 2.04 mmol) and racemic ((1R*,2S*,3R*,4S*)-3-aminobicyclo[2.2.1]heptan-2-yl)methanol hydrochloride (435 mg, 2.45 mmol) in NMP (5 ml) was treated with DIPEA (1.07 ml, 6.13 mmol), stirred at 100° C. for 6 h and at 180° C. (MW) for 30 min. The reaction mixture was diluted in EtOAc and washed with water (2×) and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a beige solid. (UPLC-MS 3) tR 0.53 min; ESI-MS 259.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C1COCC1.[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(-c2ccc(CCCO)cc2)nc1C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
The product of step (vi) (14.5 g, 31.3 mmol) was added to a plastic vessel and THF (150 mL) added. HF (30 mL) was added carefully to the solution and the solution stirred at room temperature for 3 hours. The mixture was poured to 600 mL of water and 5 N—NaOH added to basify the solution to pH=10-11. The solution was extracted with EtOAc and washed with water (×3). The combined EtOAc extract was dried over MgSO4, filtered and concentrated in vacuo, which afforded the subtitle compound (vii) as a yellow solid (10 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>C(#N)C>[CH2:15]([NH:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of 2-chloro-5-nitro-benzenesulfonamide (20 g, 84.52 mmol) in acetonitrile (169 mL) was treated with benzylamine (13.85 mL, 126.78 mmol), diisopropyl ethylamine (29.44 mL, 169.04 mmol) and stirred for 16 h at 55° C. The reaction was cooled to 25° C., poured into water (1.0 L) then placed in an ice bath while stirring. After 4 h a precipitate was filtered off and washed with the mother liquor to afford the desired product, 2-benzylamino-5-nitro-benzenesulfonamide (21.65 g, 70.45 mmol, 83.3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.64 (2H, d, J=4.6 Hz), 6.81 (1H, d, J=9.4 Hz), 7.23-7.44 (6H, m), 7.77 (2H, bs), 8.11 (1H, dd, J1=9.4 Hz, J2=2.3 Hz), 8.49 (1H, d, J=3.1 Hz). LC-MS (ESI) calcd for C13H13N3O4S 307.06, found 308.2 [M+H+] (100%), 615.2 [2M+H+] (81%).
Reaction SMILES: [NH2:1][C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N([C:54]([O:56][CH2:57][CH:58]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:64]2[C:59]1=[CH:60][CH:61]=[CH:62][CH:63]=2)=[O:55])[C@H](C(O)=O)CSC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S(=O)(=O)(O)O>CO>[NH:1]([C:54]([O:56][CH2:57][CH:58]1[C:59]2[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:65]2[C:70]1=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:55])[C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
and H2N-Cys(Trt)-OMe 26. 7.2 g (12.3 mmol) of Fmoc-Cys(Trt)-OH was dissolved in 70 ml of MeOH and added 1.5 ml of conc. sulfuric acid. The reaction mixture was refluxed for 4 hr, the solvent was removed. The mixture was then mixed with ethyl acetate, and washed with water, saturated NaHCO3, and brine. Removing the solvent under vacuum gave 25 as a white foamy solid. The crude product was dissolved in 20 ml of 20% piperidine solution in DMF. After 2 hr, the solvent was removed. Silicagel chromatography (CH2Cl2:MeOH=10:1) gave 4.0 g (86% two step yield) of 26 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[C:16]([S:19][CH2:20][CH3:21])=[C:15]([CH2:22][CH2:23][CH3:24])[C:14](=[O:25])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[C:16]([S:19]([CH2:20][CH3:21])=[O:36])=[C:15]([CH2:22][CH2:23][CH3:24])[C:14](=[O:25])[C:11]=3[C:12]=2[CH3:13])=[CH:26][CH:27]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCC1=C(SCC)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Solvent: ClCCl
Product: CCCC1=C(S(=O)CC)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O

Procedure:
To a solution of the product of Example 11 (247 mg, 0.66 mmol) in CH2Cl2 (30 mL) was added m-chloroperbenzoic acid (140 mg). The reaction was complete in a few minutes, and was quenched with 10% NaCO3. The organic layer was separated, dried (Na2SO4) and the crude product was chromatographed on silica gel (30% EtOAc/hexane) to give the title compound.
Reaction SMILES: [BH4-].[Na+].[Sn:3](I)([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:10]([SnH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[Sn](I)(CCCC)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCC[SnH](CCCC)c1ccccc1
Temperature: 0 °C

Procedure:
In a Schlenk tube, a suspension of NaBH4 (1.96 g, 51.9 mmol) in 50 mL of absolute ethanol was cooled at 0° C. under nitrogen. A solution of Bu2SnPhI (15.1 g, 34.6 mmol) in ethanol was then added slowly under stirring. After 3 hours at room temperature in the dark, petroleum ether was added, the solution was washed with water and dried over MgSO4. Solvents were eliminated under reduced pressure and the residue was distilled under high vacuum. A colourless oil was obtained (7.2 g, 30.8 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29]/[C:30](=[N:33]/[H])/[NH:31]O)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[O:10][N:33]=2)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: Cc1cccnc1C(=O)O
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3ncccc3C)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 12.2 %

Procedure:
3-Methyl-2-pyridinecarboxylic acid (35 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The reaction mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid 14 mg, 12%).
Reaction SMILES: [C:1]1([C:7]2([C:14]#[N:15])[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:14]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][C:10]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH2:8]1)#[N:15]
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: C1CCNC1
Product: N#CC1(c2ccccc2)CC=C(N2CCCC2)CC1

Procedure:
Using the procedure of step A at example 1 and starting from 79.6 g of 4-phenyl 4-cyanocyclohexanone and 56.8 g pyrrolidine there is obtained with a theoretical yield 4-cyano 4-phenyl 1-pyrrolidino cyclohex-1-ene.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([OH:11])[C:5]=2[CH:4]([CH2:19][C:20]([O:22]CC)=[O:21])[O:3]1.[OH-].[Li+].Cl>CCO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([OH:11])[C:5]=2[CH:4]([CH2:19][C:20]([OH:22])=[O:21])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a solution of ethyl 2-(1,4-dihydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (100 mg, 0.31 mmol) in EtOH (5 ml) was added an aqueous solution of lithium hydroxide (26.1 mg, 0.62 mmol) in water (1 mL). The reaction mixture was stirred at room temperature overnight and acidified with 1 N HCl to pH=3. The resulting mixture was extracted with EtOAc (20 mL) and combined organic layers were washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (17 mg, yield: 18%). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.13 (s, 1H), 9.19 (s, 1H), 8.54 (s, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.24 (d, J=1.2 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 5.44 (m, 1H), 3.22 (m, 1H), 2.18-2.11 (m, 1H). MS (ESI) m/z=303 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([O:11][CH3:10])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(N)c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cccc(NCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
4-Chlorobenzaldehyde (3.41 g, 27.5 mmol) was added to a cooled stirred solution of 3-methoxy aniline (3.38 g, 27.5 mmol) in anhydrous dichloromethane (120 ml). Sodium triacetoxy borohydride (8.16 g, 38.5 mmol) and acetic acid (1.57 ml, 27.5 mmol) were added and the reaction stirred under nitrogen at room temperature overnight. The reaction was quenched by the addition of 2 N sodium hydroxide (aq) and the resulting solution was extracted with dichloromethane (3×100 ml). The organic extracts were combined, washed with water (100 ml), brine (100 ml) and then concentrated in vacuo to obtain crude product. The residues were purified by flash chromatography (SiO2) eluting with petrol/dichloromethane 3:1 to afford the title compound (4.4 g, 64% yield). HPLC retention time 8.4 min Mass spectrum (ES+) m/z 248 (M+H).
Reaction SMILES: [CH3:1][O:2]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH3:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Ca+2].[Cl-]>ClCCCl.CCCCCC>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:1]=[O:2])=[CH:21][C:20]=1[CH2:25][CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1ccccc1OCc1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCCCCC
Product: CCc1cc(C=O)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In 25 g of 1,2-dichloroethane was dissolved 3.25 g (28 mmol) of dichloromethyl methyl ether, and the solution was chilled with ice-water. Here was added dropwise 7.36 g (28 mmol) of anhydrous tin (IV) chloride, and the mixture was stirred for 10 minutes. Here was added dropwise 5.00 g (23.55 mmol) of 1-benzyloxy-2-ethylbenzene obtained in Step 2 dissolved in 1,2-dichloroethane, and the mixture was stirred at ambient temperature for 5 hours. To the reaction mixture, aqueous solution of calcium chloride was added dropwise at 20° C. or below, 15 g of hexane was added, the organic layer was washed with water, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane=1:10, SiO2) to yield the desired product, 4-benzyloxy-3-ethylbenzaldehyde, as yellow liquid (3.17 g, Yield: 56%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][CH:32]1[CH2:34][O:33]1>CC(N(C)C)=O.CCOCC.O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:31][CH:32]1[CH2:34][O:33]1)[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2
Reactant: BrCC1CO1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(OCC3CO3)cc21
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.15 g, 0.47 mmol) in DMA (5 mL) was added Cs2CO3 (0.46 g, 1.41 mmol). After stirring the mixture for 3 hours, 2-bromomethyloxirane (0.13 g, 0.94 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with ether and water and the layers were separated. The aqueous layer was extracted with ether (3×) and the combined organic layers were washed with water and brine, and dried over Na2SO4. The crude product was concentrated under reduced pressure and used in the next reaction without further purification (0.135 g, 77% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][C:13](=O)[C:12]2[C:11]3[C:10]([C:16]([O:18]C)=O)=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3]1.O.NN.C1C2NC3C=CC=C4C(=O)[NH:37][N:38]=C(C=2C=34)CC1>>[CH3:1][N:2]1[CH2:3][C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:16](=[O:18])[NH:37][N:38]=[C:13]([C:12]=2[C:11]=34)[CH2:14]1
Reactant: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C)C3
Agent: NN
Solvent: O
Product: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 44 was prepared from Methyl 2-methyl-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate according to the procedure similar to that for Compound 1. 1H NMR (DMSO-d6) δ 11.7 (s, 1H), 9.87 (s, 1H), 7.43 (d, 1H, J=8.0 Hz), 7.39 (d, 1H, J=7.6 Hz), 7.14 (dd, 1H, J=8.0, 7.6 Hz), 3.70 (s, 2H), 3.13 (s, 2H), and 2.39 (s, 3H). MS (ESI) m/e [M+1]+ 241.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:21][C:22](=[O:24])[CH3:23])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(SCC(C)=O)cc1
Temperature: 25 °C

Procedure:
To a solution of (4-mercaptophenyl)-acetic acid ethyl ester (10 g, 0.051 mol) in 150 mL of acetone is added potassium carbonate (anhydrous, 8.51 g, 0.061 mol) at 0° C., followed by dropwise addition of chloroacetone (5 mL, 0.061 mol) in 10 mL of acetone at 0° C. The reaction is then maintained at RT for 2 h. The reaction is filtered and the filtrate is concentrated under vacuum. The residue thus obtained is diluted with 15 mL of water and extracted with ethyl acetate (2×50 mL). The organic layer is then washed with water and brine, dried over sodium sulfate, filtered and evaporated under vacuum to give [4-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1.C(=O)(O)[O-].[Na+].CS(C)=O>CCOC(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22]([N:35]4[CH2:36][C:33]([F:37])([F:32])[CH2:34]4)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ccc1Br
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A reaction vessel was charged with (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (50 mg, 0.097 mmol), 3,3-difluoroazetidine hydrochloride (125 mg, 0.966 mmol) and sodium bicarbonate (162 mg, 1.932 mmol). DMSO (2 mL) was added. The reaction was heated to 150° C. under an atmosphere of N2. After 16 hours, the reaction was cooled to r.t., diluted with EtOAc (40 mL), and washed with water and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 80% EtOAc/hexanes afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-bromo-6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one contaminated with a minor impurity. This material was used in subsequent reactions without further purification. LCMS=575.9 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.78 (s, 2H), 7.63 (d, J=8.7 Hz, 1H), 6.24 (d, J=8.7 Hz, 1H), 5.75 (d, J=8.4 Hz, 1H), 4.87 (d, J=17.1 Hz, 1H), 4.23-4.40 (m, 6H), 0.79 (d, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[C:13]([CH:14]=O)[C:12]([OH:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[CH2:1]([C:9]1[CH:16]=[C:13]([CH:14]=[N:20][CH2:19][CH2:18][N:21]=[CH:14][C:13]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:16]=2)[OH:17])[C:12]([OH:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(O)c(C=O)c1
Reactant: NCCN
Product: CCCCCCCCc1ccc(O)c(C=NCCN=Cc2cc(CCCCCCCC)ccc2O)c1

Procedure:
NN1 -di(5-octylsalicylidene) ethylene diamine was prepared by codissolving stoichiometric quantities of 5-octylsalicylaldehyde (prepared as described above) and ethylene diamine in hot absolute alcohol. After heating for 15 minutes the mixture was cooled to precipitate the Schiff's base (ketimine) in the form of yellow plates m p 157°-158° C.
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[F:56][C:57]([F:68])([F:67])C1C=CC(C(Cl)=O)=CC=1.C(N(CC)CC)C>O1CCCC1>[F:56][C:57]([F:68])([F:67])[C:32]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH:9]([C:11]2[N:16]=[N:15][C:14]([NH:17][C:18]3[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=3)=[N:13][CH:12]=2)[CH3:10])=[O:7])=[CH:4][CH:33]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(C(F)(F)F)cc3)nn2)cc(OC)c1OC
Yield: 59 %

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (295 mg, 0.97 mmol), 4-(trifluoromethyl)benzoyl chloride (0.16 mL, 1.08 mmol), and triethylamine (0.168 mL, 1.20 mmol) in tetrahydrofuran (4 mL) gave 4-(trifluoromethyl)-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (284 mg, 59%) as a yellow solid. MS m/z 477 (M+1).
Reaction SMILES: [NH2:1]CC1(CC2CC2)CCN(S(NCC)(=O)=O)CC1.Cl[C:20]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:21]=1[C:22](Cl)=[O:23]>>[F:29][C:28]1[CH:20]=[C:21]([C:25]([F:30])=[CH:26][CH:27]=1)[C:22]([NH2:1])=[O:23]
Reactant: O=C(Cl)c1c(F)ccc(F)c1Cl
Reactant: CCNS(=O)(=O)N1CCC(CN)(CC2CC2)CC1
Product: NC(=O)c1cc(F)ccc1F

Procedure:
4-Aminomethyl-4-(cyclopropylmethyl)-N-ethylpiperidine-1-sulfonamide (I-10) was treated with 2-chloro-3,6-difluorobenzoyl chloride according to the procedure outlined above to afford 2-chloro-N-{[4-cyclopropylmethyl)-1-[(ethylaminosulfonyl)]-piperidin-4-yl]methyl}-3,6-difluorobenzamide (I-12). 1H NMR (500 MHz, CD3OD): δ 7.37-7.31 (m, 1 H), 7.24-7.18 (m, 1 H), 3.53 (s, 2 H), 3.26-3.18 (m, 4 H), 3.04 (q, J=7.2 Hz, 2 H), 1.69 (t, J=5.7 Hz, 4 H), 1.37 (d, J=6.7 Hz, 2H), 1.16 (t, J=7.2 Hz, 3 H), 0.81-0.73 (m, 1 H), 0.50 (q, J=5.9 Hz, 2 H), 0.08 (q, J=4.8 Hz, 2 H); MS 450 (M+H).