Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[CH2:25][NH:26][S:27]([C:30]3[C:31]([CH3:44])=[C:32]([CH3:43])[C:33]4OC(C)(C)[CH2:36][CH2:35][C:34]=4[C:41]=3C)(=[O:29])=[O:28])[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[OH:46][CH2:47][C@H](NS(C1C=CC2C(=CC=CC=2)C=1)(=O)=O)C(O)=O.N[C@H](C(O)=O)CO.C1C2C(=CC=CC=2)C=CC=1S([Cl:86])(=O)=O>>[ClH:86].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[C@@H:25]([NH:26][S:27]([C:30]3[CH:31]=[CH:44][C:33]4[C:34](=[CH:35][CH:36]=[CH:43][CH:32]=4)[CH:41]=3)(=[O:29])=[O:28])[CH2:47][OH:46])[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)[C@H](CO)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Agent: Cl
Agent: N[C@@H](CO)C(=O)O
Product: Nc1nccc2cc(CC(NC(=O)[C@H](CO)NS(=O)(=O)c3ccc4ccccc4c3)C(=O)N3CCCCC3)ccc12

Procedure:
The procedure described for 5c was used. Deprotection of Sa and coupling with (2S)-3-hydroxy-2-[(2-naphthalenylsulfonyl)amino]propanoic acid (prepared from L-serine and 2-naphthalenylsulfonylchloride using the procedure described for 5b) yielded 7. 1H-NMR 200 MHz (CD3OD) δ: 1.12-1.58 (6H, m), 2.57-2.69 (1H, m) 2.95-3.95 (8H, m), 4.9-5.1 (1H, m), 7.11-7.22 (1H, m), 7.43-8.16 (9H, m), 8.24-8.34 (1H, m), 8.41-8.45 (1H, m).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])#[N:12]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11]#[N:12])(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1C#N

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g) and 2-cyanobenzenesulphonyl chloride (0.24 g).
Reaction SMILES: N#N.C[Si](C)(C)[S:5][Si](C)(C)C.C[O-].[Na+].[CH3:15][C:16]1([C:21]2[O:25][C:24]([CH2:26][C:27]#[N:28])=[CH:23][CH:22]=2)[O:20][CH2:19][CH2:18][O:17]1>CN(C=O)C.O>[CH3:15][C:16]1([C:21]2[O:25][C:24]([CH2:26][C:27]([NH2:28])=[S:5])=[CH:23][CH:22]=2)[O:17][CH2:18][CH2:19][O:20]1
Reactant: CC1(c2ccc(CC#N)o2)OCCO1
Reactant: C[Si](C)(C)S[Si](C)(C)C
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccc(CC(N)=S)o2)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethyldisilthiane (9.45 mL, 45.07 mmol) was added dropwise to a solution of NaOMe (2.51 g, 45.07 mmol) in dry DMF (40 mL) and the reaction mixture was stirred at rt for 15 min. This dark blue solution was then added to a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-acetonitrile (3.48 g, 18.03 mmol) in DMF (30 mL) and the reaction mixture was stirred for 16 h at rt. Water (300 mL) was then added and the mixture was extracted twice with EA (300 mL). The combined org. phases were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.18. LC-MS-conditions 02: tR=0.74 min, [M+H]+=228.44.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:22]([O-:24])=[O:23])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH:7]=O)[CH3:2].[CH3:25]/[C:26](/[NH2:30])=[CH:27]\[C:28]#[N:29].[CH2:31]([CH:34]1[CH2:39][C:38](=[O:40])[CH2:37][C:36](=O)[CH2:35]1)[CH2:32][CH3:33]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]2[C:37]3[C:38](=[O:40])[CH2:39][CH:34]([CH2:31][CH2:32][CH3:33])[CH2:35][C:36]=3[NH:30][C:26]([CH3:25])=[C:27]2[C:28]#[N:29])[CH:9]=[C:10]([N+:22]([O-:24])=[O:23])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH3:2]
Reactant: C/C(N)=C\C#N
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1OCc1cccc(OC)c1
Reactant: CCCC1CC(=O)CC(=O)C1
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(OCC)c(OCc2cccc(OC)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-ethoxy-4-(3-methoxy-benzyloxy)-5-nitro-benzaldehyde (40 mg), 3-aminocrotonitrile (10 mg) and 5-propylcylcohexane-1,3-dione (19 mg) in ethanol (2 ml) was stirred at 80° C. for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/1 (v/v) as eluent.
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]2[CH2:12][OH:13])[C:4]2[N:14]=[C:15]([NH2:19])[N:16]=[C:17](N)[C:3]=2[N:2]=1.P([O-])([O-])([O-])=[O:21]>[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O>[CH:1]1[N:5]([C@@H:6]2[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]2[CH2:12][OH:13])[C:4]2[NH:14][C:15]([NH2:19])=[N:16][C:17](=[O:21])[C:3]=2[N:2]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@H]3CO)c2n1
Reactant: O=P([O-])([O-])[O-]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Product: Nc1nc(=O)c2ncn([C@@H]3O[C@H](CO)[C@H]3CO)c2[nH]1
Temperature: 37 °C
Reaction time: 50 h

Procedure:
After 2.0 g of 2-amino-OXT-A was dissolved in 300 ml of 1/10M phosphate buffer (pH 6.5), 200 units of 5'-adenylic acid deaminase (manufactured by Sigma Co., A-1907) were added to the solution followed by stirring at 37° C. for 50 hours. After the reaction solution was passed through a column packed with MCI® GEL CHP 20 (300 ml) and the reaction products were adsorbed onto it, the products were eluted by water. Fractions showing an Rf value of about 0.42 in silica gel TLC [developing solvent: n-butanol-acetic acid-water (4:1:2)] were collected and concentrated to dryness under reduced pressure to give 1.8 g of OXT-G as colorless crystals (yield, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[CH3:30])=[O:12])[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:44]([NH2:47])([CH3:46])[CH3:45].C(OCC)(=O)C>COC(C)(C)C>[CH3:45][CH:44]([NH:47][C:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:29])([C:21]([F:22])([F:23])[F:24])[C:25]([F:28])([F:27])[F:26])=[CH:16][C:15]=1[CH3:30])=[O:12])=[O:10])[CH3:46]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1ccnc(Cl)c1C(=O)O
Reactant: CC(C)N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1ccnc(Cl)c1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
In 10 ml of t-butyl methyl ether was dissolved 500 mg of 2-chloro-4-[4-(heptafluoro-2-propyl)-2-methylphenyl]aminocarbonyl-3-pyridinecarboxylic acid, followed by adding thereto 340 mg of ok trifluoroacetic anhydride, and the resulting mixture was stirred at room temperature for 2 hours. After the disappearance of the starting material was confirmed by TLC, 330 mg of isopropylamine was added to the mixture, followed by stirring at room temperature for another 2 hours. After completion of the reaction, ethyl acetate was added and the reaction solution was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography using ethyl acetate/n-hexane as an eluent, to obtain 460 mg of the desired compound as white crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([F:9])[CH:7]=[O:8].[Na].C1(S)C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[C:6](\[F:9])/[CH:7]=[O:8]
Reactant: O=CC(F)=CCCCCl
Agent: Sc1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C/C(F)=C/CCCCl

Procedure:
2.35 Grams of 6-chloro-2-fluoro-2-hexenal (E form : Z form =6.8 : 1) was dissolved in 20 ml of dry toluene, and after adding 10 mg of the sodium salt of thiophenol, the resulting solution was heated under reflux for 25 hours with stirring. Thereafter, 10 ml of water was added to the reaction solution, and the toluene layer was separated. The aqueous layer was extracted twice with ether, and the ether extracts were combined with the above toluene layer. This mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 2.35 g of (Z)-6-chloro-2-fluoro-2-hexenal.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)=[CH:48][C:49]4[N:54]([CH2:55][C:56]([NH2:58])=[O:57])[C:53](=[O:59])[CH2:52][O:51][C:50]=4[N:60]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)=[CH:48][C:49]4[N:54]([CH2:55][C:56]([NH2:58])=[O:57])[C:53](=[O:59])[CH2:52][O:51][C:50]=4[N:60]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC(N)=O)C(=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: NC(=O)CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 116.7 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(1-(2-amino-2-oxoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (10 mg, 0.02 mmol) was reacted to afford the title compound (10 mg, quantitative). LCMS (Method A): RT=3.43 min, M-NH2=412. 1H NMR (500 MHz, MeOD): 7.39 (2H, d), 7.36 (2H, d), 7.34 (1H,S), 7.28-7.26 (3H, m), 7.18-7.17 (m, 2H), 5.01 (2H, s), 4.72 (2H, s), 2.76-2.70 (m, 2H), 2.57-2.51 (m, 2H), 2.25-2.16 (m, 1H), 1.98-1.89 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:16][CH2:15][CH:14]([O:17][S:18]([NH:21][CH2:22][CH2:23][O:24]C(=O)C)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Li+].C(OCC)(=O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:12][CH2:13][CH:14]([O:17][S:18](=[O:19])(=[O:20])[NH:21][CH2:22][CH2:23][OH:24])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCNS(=O)(=O)OC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(NCCO)OC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Example 116 (54 mg, 0.1 mmol) in tetrahydrofuran (2 mL) was added lithium hydroxide (35 mg, 1.5 mmol) in water (2 mL) and the mixture stirred for 2 hours. Ethyl acetate (20 mL) was added, the solution washed with saturated aqueous ammonium chloride (10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica eluting with ethyl acetate:iso-hexane 1:1, to afford the title compound. (33 mg).
Reaction SMILES: [C:1]1([C@@H:7]2[O:11][N:10]=[C:9]([C:12]([C:14](=O)C)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>ClCCCl.ClC(Cl)C.O>[Br:17][CH2:14][C:12]([C:9]1[CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:11][N:10]=1)=[O:13]
Reactant: CC(=O)C(=O)C1=NO[C@@H](c2ccccc2)C1
Reactant: BrBr
Solvent: O
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: O=C(CBr)C1=NO[C@@H](c2ccccc2)C1
Temperature: 30 °C
Yield: 72.9 %

Procedure:
1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazoyl]ethanone (3.2 g, 16.7 mmol) was dissolved in 1,2-dichloroethane (15 mL), and a solution of bromine (2.13 g, 13.3 mmol) in dichloroethane (5 mL) was added over 30 minutes while maintaining the temperature of the reaction mixture at about 30° C. The reaction mixture was diluted with water (10 mL), and the organic layer was concentrated under reduced pressure and purified by medium-pressure liquid chromatography using 35% of dichloromethane in hexanes as eluant to give 2.6 g of the title compound as a white solid, melting at 31-33° C.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:24][CH3:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:24]([CH3:25])[C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2ccccc2OC)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution of 0.30 g (0.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.19 g (1.31 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt with ethanolic HCl to yield 0.41 g (89%) of the title compound as a white solid; mp=222-224° C.; MS(+)ESI m/z=456 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[CH3:16])[CH:7]=[C:6]([CH3:17])[CH:5]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.C(OCC)(=O)C>[CH3:25][S:26]([O:1][CH2:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[CH3:16])[CH:7]=[C:6]([CH3:17])[CH:5]=1)(=[O:28])=[O:27]
Reactant: Cc1cc(CCO)nc(-n2c(C)ccc2C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(CCOS(C)(=O)=O)nc(-n2c(C)ccc2C)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 100.1 %

Procedure:
A solution of 2.00 g (8.68 mmol) of 6-(2-hydroxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 58, Step A) and 1.82 mL (1.32 g, 13.1 mmol) of triethylamine in 20 mL of dichloromethane was cooled to 0° C. and 0.68 mL (1.0 g, 8.8 mmol) of methanesulfonyl chloride was added over 5 min. The mixture was stirred another 25 min at 0° C., diluted with 70 mL of ethyl acetate, and washed with 30 mL each of water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate), decanted, and evaporated to give 2.68 g (100% yield) of 6-(2-methanesulfonyloxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine as a viscous pink oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]2([CH3:35])[CH3:34]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:31]4[CH:22]=[CH:23][C:24]5[C:25]([CH3:35])([CH3:34])[CH2:26][CH2:27][C:28]([CH3:33])([CH3:32])[C:29]=5[CH:30]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Product: CC1(C)CCC(C)(C)c2cc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)ccc21

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (140.0 mg, 0.5239 mmol) in a manner analogous to Step 2d and was isolated as a yellow foam (0.049 g, 30%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 1.1 Hz, 1H), 8.29-8.25 (m, 2H), 8.10-8.05 (m, 2H), 7.65 (dd, J=7.5, 1.2 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.36-7.27 (m, 2H), 7.00 (dd, J=7.2, 7.2 Hz, 1H), 6.76 (s, 1H), 3.10 (s, 3H), 1.74-1.66 (m, 4H), 1.33 (s, 6H), 1.28 (s, 6H). MS=475 (MH)+.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:18][C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:13]=2[C:12]2[O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)ccc1c3ccccc3oc21
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2c3ccccc3oc2c2ccccc12
Temperature: 60 °C
Yield: 82 %

Procedure:
32.7 g of benzo[b]naphtho[2,1-d]furan was dissolved in 300 mL of N,N-dimethylformamide. Then, 50 mL of a N,N-dimethylformamide solution of 28.0 g of N-bromosuccinimide was added, and the resulting reaction solution was stirred with heating at 60° C. for 5 hours. After cooling to room temperature, the reaction solution was poured in 2 L of water. Solids thus obtained were sequentially washed with methanol, water and methanol. The resulting crude product was purified by means of silica gel column chromatography, whereby 36.5 g (yield: 82%) of 5-bromobenzo[b]naphtho[2,1-d]furan was obtained.
Reaction SMILES: [F-:1].[K+].COCCOCCOC.[C:12]([C:19]([F:21])=O)([C:15]([F:18])([F:17])[F:16])([F:14])[F:13].S([O:27][CH3:28])(OC)(=O)=O>O>[C:19]([O:27][CH3:28])([C:12]([C:15]([F:18])([F:17])[F:16])([F:14])[F:13])([F:21])[F:1]
Reactant: O=C(F)C(F)(F)C(F)(F)F
Reactant: COS(=O)(=O)OC
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: COC(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A jacketed one liter round bottom flask was equipped with an overhead stirrer, a solid carbon dioxide/acetone condenser, and an addition funnel. The flask was charged with spray-dried potassium fluoride (85 g, 1.46 mol) and anhydrous diethylene glycol dimethyl ether (375 g) and was then cooled to about −20° C. using a recirculating refrigeration system. C2F5COF (196 g, 1.18 mol) was added to the flask over a period of about one hour. The flask was then warmed to about 24° C., and dimethyl sulfate (184.3 g, 1.46 mol) was then added dropwise via the addition funnel over a 45 minute period. The resulting mixture was then stirred at room temperature overnight. Water (a total of 318 mL) was then added dropwise to the mixture. The mixture was transferred to a one liter round bottom flask, and the resulting product ether was azeotropically distilled. The lower product phase of the resulting distillate was separated from the upper aqueous phase, was washed once with cold water, and was subsequently distilled to give 180 g of product (b.p. 360° C.; >99.9% purity by GLC). The product identity was confirmed by GCMS and by 1H and 19F NMR.
Reaction SMILES: ClC1N=CN=C(C(NC2C=CC(S(NCC(OC)=O)(=O)=O)=CC=2C)=O)C=1.C(NC(C)C)(C)C.C1(CNC2CCCCC2)CC1.[CH:45]1([N:51]([CH2:77][CH:78]2[CH2:80][CH2:79]2)[C:52]2[N:57]=[CH:56][N:55]=[C:54]([C:58]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([S:67]([NH:70][CH2:71][C:72]([O:74]C)=[O:73])(=[O:69])=[O:68])=[CH:63][C:62]=3[CH3:76])=[O:59])[CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C1(N(CC2CC2)C2N=CN=C(C(NC3C=CC(S(NCC(OCC)=O)(=O)=O)=CC=3C)=O)C=2)CCCCC1>C(O)C>[CH:45]1([N:51]([CH2:77][CH:78]2[CH2:79][CH2:80]2)[C:52]2[N:57]=[CH:56][N:55]=[C:54]([C:58]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([S:67]([NH:70][CH2:71][C:72]([OH:74])=[O:73])(=[O:69])=[O:68])=[CH:63][C:62]=3[CH3:76])=[O:59])[CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Agent: C1CCC(NCC2CC2)CC1
Agent: CCOC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Agent: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: Cc1cc(S(=O)(=O)NCC(=O)O)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 160 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A solution of methyl 2-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate (Intermediate 33, 123 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (56.6 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give a mixture of methyl 2-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate and ethyl 2-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate which was used directly without any further purification. The residue was redissolved in methanol (10 ml) and tetrahydrofuran (10 ml) and treated with 5 N NaOH solution (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with conc. HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid (136 mg, 87%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33].[OH-].[Na+]>ClCCl>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1)=[O:33]
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C

Procedure:
6.0 g (20.7 mmol) N-(4-piperidine-4-yl-butyl)-3-(pyridine-3-yl)-propionamide and 2.1 g (20.7 mmol) TEA are dissolved in 30 ml abs. dichloromethane and cooled to ca. 0° C. under moisture extraction. 3.95 g (20.7 mmol) 2-naphthoylchloride are dissolved in 40 ml abs. dichloromethane and added dropwise under ice cooling. The mixture is stirred without further cooling at RT overnight. Subsequently, the batch is made basic by the addition of 10% sodium hydroxide solution and washed twice with a small amount of water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is chromatographically purified with CHCl3/CH3OH (96/4). Yield of colorless resin: 5.4 g (59%).