Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][C:12](=[N:46]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([C:34]([NH:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.CC(O)=O.[ClH:61]>[Pd].CO>[ClH:61].[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]([NH:18][C@@H:17]([C:34]([NH:36][C@H:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][OH:39])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:46])=[O:33])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N=C(NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(g) above from (R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(R)-N-(2-hydroxy-1-phenylethyl)-arginine amide (0.250 g; from step (e) above), 10% Pd/C (200 mg) and, instead of HOAc, 50 mL of MeOH with 1 mL of concentrated HCl, yielding 69 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30]>O1CCCC1>[N+:29]([C:20]1[CH:21]=[C:22]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:23]=[CH:24][C:19]=1[O:1][CH2:2][CH:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1)([O-:31])=[O:30]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2CCNCC2)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.300 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.223 g). After stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.276 g) was added and reaction stirred at room temperature. After 1 hour the reaction was partitioned between water (25 mL) and dichloromethane (50 mL) and the reaction quenched with 1N aqueous HCl (5.57 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. Treatment with HCl (4.0M in dioxane, 2 mL) and methanol (2 mL) for 1 hour, followed by concentration, trituration with dichloromethane and filtration gave the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:25](=[O:28])([O-])[O-:26].[Na+].[Na+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([N:21]4[CH2:22][C:15]5[CH:16]=[C:17]6[O:26][CH2:25][O:28][C:18]6=[CH:13][C:14]=5[CH2:10]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)c(N2Cc3cc4c(cc3C2)OCO4)c(C)c2c1OC(C)(C)C2c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (835.5 mg, 2.58 mmol) in tetrahydrofuran (20 ml) were added 5,6-bis(chloromethyl)-1,3-benzodioxazole (574.5 mg, 2.62 mmol), sodium carbonate (832.8 mg, 7.88 mmol), and tetrabutylammonium iodide (481.6 mg, 1.30 mmol) and the mixture was refluxed with heating for 23 hours. The reaction mixture was cooled down to room temperature and then poured into ice water. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from isopropyl ether to obtain 395.0 mg (33% yield) of the title compound. Melting point: 175-177° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-dimethylamino-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M21) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (158 mg).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:3][C:4]2[C:10]([N+:16]([O-:18])=[O:17])=[C:9]([O:11][C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(OC(F)(F)F)ccc2nc(Cl)sc12
Temperature: 60 °C

Procedure:
10 g of 2-chloro-6-trifluoromethoxybenzothiazole are added dropwise over one hour to a mixture, cooled to 10° C., of concentrated sulphuric acid (50 cm3) and concentrated nitric acid (25 cm3). The mixture is then heated for one hour at 60° C. After cooling, the mixture is poured into an ice/water mixture (1/1 by weight) and extracted with 3 times 100 cm3 of chloroform. The organic phases are dried over magnesium sulphate and concentrated under vacuum (2.7 kPa). The residue is purified by flash chromatography with a chloroform/cyclohexane mixture (4/6 by volume) as eluent. 6.4 g of 2-chloro-7-nitro-6-trifluoromethoxybenzothiazole are thus obtained, melting at 64° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]>>[CH2:34]([N:38]1[CH2:43][CH2:42][N:41]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 21 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.1 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[C:4]([O:17][C:18]([F:21])([F:20])[F:19])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:12])[CH3:11])=[C:4]([O:17][C:18]([F:21])([F:19])[F:20])[CH:3]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(O)cc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CO[Si](C)(C)C(C)(C)C)c(OC(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-hydroxy-1-(tert-butyldimethylsilyloxymethyl)-2-trifluoromethoxybenzene (3.2 g, 10 mmol) from Step 4 above and triphenylphosphine (3.9 g, 15 mmol) in THF (50 mL) at 0° C. was added a solution of N-tert-butyloxycarbonyl-4-piperidinol (3.0 g, 15 mmol) and DEAD (2.6 g, 15 mmol) in THF (25 mL) dropwise over a period of 1 h. The mixture was stirred at 0° C. for 3 h and then at ambient temperature for 12 h. The solvent was removed under reduced pressure and the residue was suspended in ether. The solid triphenylphosphine oxide was removed by filtration and the filtrate was purified by pressurized silica gel column chromatography using a gradient elution of 5-10% EtOAc:hexanes as eluant to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-1-(tert-butyldimethylsilyloxy-methyl)-2-trifluoromethoxybenzene as a colorless gum.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:41])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:33][C:32]3[CH:31]=[N:30][N:29]([CH3:34])[C:28]=3[N:27]([CH3:35])[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]2=3)=[O:23])=[CH:18][C:17]=1[CH3:40])(C)(C)C>ClCCl>[CH3:34][N:29]1[C:28]2[N:27]([CH3:35])[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:41])=[O:12])=[C:17]([CH3:40])[CH:18]=3)=[O:23])[CH2:33][C:32]=2[CH:31]=[N:30]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (2 ml) was added to 3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propionic acid tert-butyl ester from Example E80.1 (46 mg, 0.10 mmol) in dichloromethane (5 ml). The mixture was stirred for 2 h at room temperature then concentrated in vacuo to yield the title compound (40 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[F:23][C:24]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:25]=1[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:23][C:24]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:25]=1[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1
Reactant: CCCCCCCCCNCc1ccc(F)cc1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.120 g, 0.40 mmol) in methylene chloride (5.0 mL) were added (N-(2,4-difluorobenzyl)-N-nonylamine hydrochloride (0.173 g, 0.57 mmol), DMAP (0.058 g, 0.45 mmol), and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.085 g, 0.45 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (50 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.117 g (53%) of a colourless oil.
Reaction SMILES: [Na+].[Cl-].C[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[C:9]([OH:11])[CH:10]=1.[CH3:22]C(C)=CCC1C=C2C(=CC=1O)OC(C1C=C(O)C=C(O)C=1)=C2>CO>[CH3:22][O:11][C:9]1[CH:10]=[C:5]([OH:4])[CH:6]=[CH:7][C:8]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1
Reactant: CC(C)=CCc1cc2cc(-c3cc(O)cc(O)c3)oc2cc1O
Reactant: COc1ccc(CCCc2ccc(O)cc2)c(O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(O)ccc1CCCc1ccc(O)cc1

Procedure:
Colorless needles; mp 88-89° C.; UV (MeOH) λmax (log ε) 266 (3.11), 239 (3.10) nm; IR (NaCl) γmax 3335, 2954, 1614, 1508, 1456 cm−1; 1H NMR (CD3OD, 300 MHz) δ 1.76 (2H, m, H-2), 2.49 (4H, m, H-1 and H-3), 3.74 (3H, s, OCH3), 6.29 (1H, dd, J=2.4 and 8.1 Hz, H-5′), 6.38 (1H, d, J=2.4 Hz, H-3′), 6.68 (2H, d, J=8.5 Hz, H-3″), 6.86 (1H, d, J=8.1 Hz, H-6′), 6.98 (2H, d, J=8.5 Hz, H-2″); 13C NMR (CD3OD, 75 MHz) δ 30.3 (C-1), 33.5 (C-2), 35.8 (C-3), 55.6 (OCH3), 99.7 (C-3′), 107.5 (C-5′), 116.0 (C-3″), 122.8 (C-1′), 130.3 (C-2″), 131.1 (C-6′), 134.8 (C-1″), 156.1 (C-4″), 157.6 (C-4′), 159.6 (C-2′); EIMS m/z 258 (M+, 52), 151 (18), 137 (100), 134 (20), 107 (48).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC(C)(C#N)S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CC(C)(C#N)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile. MS (ESI): mass calcd. for C20H17FN4O2S, 396.11; m/z found, 397.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 8.19 (d, J=7.9, 1H), 7.94 (m, 1H), 7.84 (m, 1H), 7.59 (m, 1H), 7.52 (d, J=7.5, 1H), 7.40 (dd, J=11.8, 1.1, 1H), 7.31 (dd, J=7.9, 1.4, 1H), 1.51 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.[N:21]#[C:22][NH2:23].[OH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26].C(O)(C(F)(F)F)=O>C1COCC1>[OH:27][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24].[C:22](=[NH:21])([O:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=2)=[CH:12][CH:11]=1)[NH2:23]
Reactant: N#CN
Reactant: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 59.7 %

Procedure:
To a solution of 2-(4-(3-(trifluoromethyl)phenoxy)phenyl)ethanol (1.395 g, 4.94 mmol) and cyanamide (0.249 g, 5.93 mmol) in THF (15 mL) was added triflic acid (0.527 mL, 5.93 mmol) under argon. The mixture was heated at 55° C. for 3 h. The mixture was purified by a reverse phase biotage with TFA affording the title compound (1.4 g, 59.8% yield). LCMS: rt=1.23 min, [M+H+]=325
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[C:27]#[N:28])=[C:10]([CH3:31])[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:27]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][C:11]1[CH:29]=[CH:30][C:8]([C:6]([OH:7])=[O:5])=[CH:9][C:10]=1[CH3:31])[O:20][CH2:19][CH2:18][CH:17]2[C:23]([O:25][CH3:26])=[O:24])#[N:28]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3C)c(C#N)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3C)c(C#N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Methyl 7-(4-(tert-butoxycarbonyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylate was taken up in dichloromethane (10 mL). To the solution was added 2 ml TFA and the solution was stirred at ambient temperature for 2 hours. The reaction was concentrated and the crude material was purified over silica gel, eluting with 2-3% methanol/dichloromethane, to provide the desired product (0.103 g, 89%).
Reaction SMILES: [CH:1]([S:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:6])([CH3:3])[CH3:2].[H][H]>C(O)C.[Ni]>[CH:1]([S:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])[CH3:6])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)SC(C)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(C)SC(C)c1ccccc1N
Yield: 87.1 %

Procedure:
44 g (0.188 mol) 1-[1-(isopropylthio)ethyl]-2-nitrobenzene (VII-1) are dissolved in 250 ml ethanol, mixed with 3 g Raney nickel and hydrogenated in the autoclave for 6 hours at room temperature with 3 bar of hydrogen. After 6 hours another 3 g Raney nickel are added and hydrogenation is continued for another 16 hours at room temperature with 3 bar hydrogen. The catalyst is then removed by filtration and the solvent removed under vacuum. The crude product is purified by column chromatography (silica gel, 3:1 hexane/methyl t-butyl ether). 32 g (97.3% purity by HPLC, 84.4% theoretical yield) of 2-[1-(isopropylthio)ethyl]aniline are obtained as a yellow oil [logP (pH 2.3)=2.45].
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO.O>[CH2:1]([N:5]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(C=O)cnc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCn1c(CO)cnc1-c1ccccc1

Procedure:
Aldehyde 102 is dissolved in methanol (150 mL). Sodium borohydride (3 g) is added in portions. After the addition was complete, the reaction is diluted with water and concentrated. The residue is dissolved in ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. The product is purified by flash chromatography on silica gel (5% MeOH/CHCl3) to give 4.17 g of 103 as a cream colored solid. 1H-NMR (400 MHz, CDCl3): δ 0.79 (3H, t, d=7.4), 1.18 (2H, m, d=7.4), 1.60 (2H, m, d=7.6), 4.03 (2H, dd, d=7.6), 4.56 (2H, s), 6.84 (1H, s), 7.39–7.50 (3H, m),7.50–7.53 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:16])([F:15])[CH2:11][N:12]=[C:13]=[S:14]>C(#N)C>[F:9][C:10]([F:16])([F:15])[CH2:11][NH:12][C:13](=[S:14])[NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: Nc1cncc(Cl)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: FC(F)(F)CNC(=S)Nc1cncc(Cl)n1
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A solution of 2-amino-6-chloropyrazine (1 g.) in warm acetonitrile (15 ml.) was cooled to room temperature. Trifluoroethylisothiocyanate (1.6 g.) was added and the mixture stirred overnight. Further trifluoroethylisothiocyanate (1.6 g.) was added, and the mixture warmed gently on a steam bath for 2 hours, then heated under reflux for 2 hours. The mixture was allowed to cool and evaporated to dryness to yield a brown solid. This was washed with water, 2N HCl solution, water again, and sucked dry. Recrystallisation from boiling toluene diluted with petroleum ether (b.p. 60°-80°) yielded colourless needles (0.77 g.) of 2-[3-(2,2,2-trifluoroethyl)thioureido]-6-chloropyrazine m.p. 170°-172°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]([CH3:14])[CH3:13])[C:6]([NH2:8])=O.O=P(Cl)(Cl)Cl.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]([CH3:13])[CH3:14])[C:6]#[N:8]
Reactant: COc1cc(C(N)=O)ccc1N(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1N(C)C
Temperature: 105 °C
Yield: 90.8 %

Procedure:
A mixture of the above benzamide (0.220 g, 1.25 mmol), POCl3 (1 mL) and diisopropylethylamine (0.5 mL) was heated to 105° C. for 16 hours and then cooled to room temperature. The solution was poured into ice water and neutralized with sodium carbonate, then extracted with EtOAc (2×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography eluting with hexanes/EtOAc (2:1) afforded 3-methoxy-4-dimethylaminobenzonitrile as an oil (0.20 g).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Br[C:38]1[CH:50]=[CH:49][C:41]([C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:40][N:39]=1>>[C:45]([NH:44][C:42](=[O:43])[C:41]1[CH:49]=[CH:50][C:38]([C:18]2[CH:17]=[CH:16][C:15]([C@@H:13]([N:9]3[CH2:8][CH2:7][C@:6]([CH2:5][C:2]([C:3]#[N:4])([CH3:36])[CH3:1])([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:11][C:10]3=[O:12])[CH3:14])=[CH:20][CH:19]=2)=[N:39][CH:40]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC(C)(C)C)cn2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 6-bromo-N-tert-butylnicotinamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.323 min, m/z=539.3; 1H NMR (CDCl3) 1.35 (s, 3H), 1.49 (s, 3H), 1.53 (s, 9H), 1.56 (m, 3H), 2.18 (m, 2H), 2.33 (m, 1H), 2.49 (m, 2H), 2.93 (m, 1H), 5.70 (m, 1H), 6.00 (m, 1H), 6.98 (d, 2H), 7.38 (m, 5H), 7.34-7.40 (m, 5H), 7.69-7.74 (m, 3H), 8.13 (m, 1H), 9.00 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]([CH3:28])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH3:28]
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=398.1 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1[N:29]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:30]=[CH:31][CH:32]=1>>[N:28]1[N:29]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:36][CH:35]=2)[N:30]=[CH:31][CH:32]=1
Reactant: Nc1ccc(Cn2nccn2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cn2nccn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1,2,3-triazol-2-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=20:1) C26H21N5O3