Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].C(N(CC)CC)C>ClCCl>[C:2]([NH:26][C@H:25]([C:24]([O:23][CH3:22])=[O:29])[CH2:27][OH:28])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
Chlorotriphenylmethane (265 g, 950 mmol) dissolved in 750 mL of dichloromethane was added dropwise to a stirred solution of L-serine methyl ester hydrochloride (148 g, 950 mmol) and triethylamine (260 mL, 1900 mmol) in 1.5 L of CH2Cl2 at 0° C. The cloudy yellow solution was stirred for 18 hours at ambient temperature. The reaction mixture was filtered to remove solids and the filtrate was washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oil. The oil was concentrated from acetonitrile and then stirred in hexanes until a precipitate formed. The resulting solid was filtered to afford 310 g of methyl N-trityl-L-serinate as an off white powder.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25](O)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:29])/[CH:26]=[CH:27]/[CH3:28]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C/C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Yield: 97.9 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.6 mL), crotonic acid (1.6 g), WSC.HCl (3.6 g), and methylene chloride (110 mL), to give the captioned compound (4.4 g, 98%) as an oily product.
Reaction SMILES: [Br:1][C:2]([Br:10])([Br:9])[CH:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>CCOCC.C([O-])(=O)C.[Na+]>[C:14]([O:8][CH:3]([C:2]([Br:10])([Br:9])[Br:1])[CH:4]=[C:5]([CH3:7])[CH3:6])(=[O:15])[CH2:13][C:12]([CH3:11])=[O:16]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)=CC(O)C(Br)(Br)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)CC(=O)OC(C=C(C)C)C(Br)(Br)Br
Yield: 99.1 %

Procedure:
1,1,1-Tribromo-4-methyl-3-penten-2-ol (6.72 g, 0.02 mole) and anhydrous sodium acetate (0.008 g) were melted together at 90°. The temperature of the mixture was then reduced to 80°, and diketene (about 2.6 ml, 0.022 mole) was added dropwise over a 10 minute period. The resulting mixture was heated at 80° for three additional hours. After cooling, the mixture was diluted with ether, and the ethereal solution was washed with 1 N aqueous hydrochloric acid and then ten times with saturated aqueous sodium bicarbonate. The washed mixture was treated with activated charcoal and dried over magnesium sulfate. Evaporation of the ether afforded 3-methyl-1-tribromomethyl-2-butenyl acetoacetate (8.34 g, 99% yield) as an oily residue.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2ccc(I)cc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)NC1CCc2ccc(I)cc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step E by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.33 (s,6H), 1.42 (s,9H), 1.80(m,1H), 2.24 (m,2H), 2.50 (m,3H), 4.45 (m,1H), 6.98 (d,8Hz,1H), 7.35 (d,2Hz,1H), 7.43 (dd;2,8Hz;1H). FAB-MS: calculated for C20H28IN3O4 501; found 502 (M+H,20%).
Reaction SMILES: Cl.[NH2:2]O.[OH:4]/[CH:5]=[C:6](\[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=1)/[CH:7]=O.C([O-])(O)=O.[Na+]>O>[O:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=2)[CH:7]=[N:2]1
Reactant: NO
Reactant: CSc1nccc(/C(C=O)=C\O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSc1nccc(-c2cnoc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of hydroxylamine hydrochloride (60.0 g, 0.86 mol) in water (2 L) was added (E)-3-hydroxy-2-(2-(methylthio)pyrimidin-4-yl)acrylaldehyde (3) (342 g, 0.714 mol) in portions. After the addition, the mixture was heated at 60° C. and stirred for 2 h. The reaction mixture was allowed to cool to room temperature and the solution was adjusted to pH about 4 by addition of 10% aq. NaHCO3. The resulting precipitate was filtered, washed with water (200 mL×2) and dried in vacuum to give 4-(isoxazol-4-yl)-2-(methylthio)pyrimidine (4) (112 g, 81.2%) as a yellow solid.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]1([C:19]([C:21]#[CH:22])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([C:21]1[CH:22]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1)(=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CC(=O)c1ccccc1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Product: O=C(c1ccccc1)c1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
6.23 g (0.039 mole) of diazooxindole and 6.6 g (0.051 mole or 1.3 equiv) of the phenylethynyl ketone prepared as in part A above (dried on a porous plate before being weighed out) are suspended in benzene (275 ml) and the mixture is refluxed under N2 for 19 hours. The reaction mixture is cooled and the precipitates that form are filtered off, washed well with anhydrous ether (150 ml) and dried in a vacuum oven at ~70° for 11/2 hours. Yield: 10.3 g, m.p. 308°-311°. Additional product of 400 mg is obtained on refluxing the filtrate for another 24 hours. Total crude yield: 94.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5](O)=[O:6].[Cl:15]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([Cl:15])=[O:6]
Reactant: ClCCl
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Temperature: 0 °C

Procedure:
A round bottom flask was charged with 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (available from Paragos Product List, 10.2 g, 47.5 mmol), dichloromethane (158 ml) and oxalyl chloride (8.29 ml, 95 mmol). The reaction mixture was cooled to 0° C. in an ice/water bath prior to the addition of N,N-dimethylformamide (0.158 ml). The solution was allowed to warm to ambient temperature overnight. The solvent was evaporated to yield the title compound as a cream solid (11.4 g). δH (CDCl3, 400 MHz): 1.44 (6H, d), 4.73 (1H, septet), 6.98 (1H, d), 8.0 (1H, dd), 7.98 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][NH2:25])[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][NH:25][S:36]([CH3:39])(=[O:38])=[O:37])[O:15][C:14]3=[O:26])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(aminomethyl)-4-phenyl-oxazolidin-2-one (14 mg, 0.035 mmol) and triethylamine (0.01 mL, 0.07 mmol) in dichloromethane (0.4 mL) at 0° C. was added mesyl chloride (0.005 mL, 0.05 mmol). The reaction mixture was stirred for 10 min and was then quenched with saturated NaHCO3 aqueous solution. Water and dichloromethane was added and the organic was washed with brine, dried (MgSO4), and concentrated. Purification by prep-LC (10-90% Acetonitrile/water (0.05% ammonium acetate) gave 5 mg (31%). 1H NMR (acetone-d6) δ (ppm) 7.45-7.51 (m, 4H), 7.32-7.42 (m, 5H), 6.94-6.97 (m, 4H), 6.66 (t, 1H, J=6.6 Hz), 5.56 (d, 1H, J=5.6 Hz), 4.51, (dd, 1H, J=10.1, 4.7 Hz), 3.59-3.72 (m, 2H), 3.04 (s, 3H). HPLC-MS calculated C23H21ClN2O5S (M+H+): 473.1, found: 473.1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:9](=[O:10])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.CC(O)C.NCCCN.CC(O)C.[OH-].[K+].[H][H]>CC(O)C>[CH3:1][CH:2]1[CH2:11][CH:9]([OH:10])[C:5](=[C:6]([CH3:7])[CH3:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Agent: NCCCN
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)=C1CCC(C)CC1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A 100 ml capacity autoclave was charged with 3.04 g (20 mmol) of pulegone, 19.1 mg (0.02 mmol) of RuCl2(PPh3)3, 0.2 M 1,3-diaminopropane 2-propanol solution (0.2 ml), 0.2 M potassium hydroxide 2-propanol solution (1.0 ml) and 2-propanol (14 ml), and the mixture was stirred at 25° C. for 3 hours under a hydrogen pressure of 2 MPa. After completion of the reaction, hydrogen was purged, the reaction solution was concentrated and then distillation was carried out under a reduced pressure to obtain 2.61 g of pulegol. The yield was 85%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:11][C:12]([NH:14][C:15]1[C:16]([S:24][CH3:25])=[N:17][C:18]([CH3:23])=[CH:19][C:20]=1[S:21][CH3:22])=[O:13].[SH:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>O>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[S:26][CH2:11][C:12]([NH:14][C:15]1[C:16]([S:24][CH3:25])=[N:17][C:18]([CH3:23])=[CH:19][C:20]=1[S:21][CH3:22])=[O:13]
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: Sc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CSc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
Potassium carbonate (46 mg, 0.33 mmol) was added to an acetonitrile (5 ml) solution of this amide (96 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 10 g, eluent—hexane:acetone=5:2) to obtain 88 mg (yield 75%) of the desired compound as a colorless crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-])=O.[CH2:13]([NH2:16])[CH2:14][CH3:15].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.C1COCC1.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:16][CH2:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCN
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCNC(=O)Nc1ccc(N)cc1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with N-4-aminophenyl-N'-propylurea to generate the title compound. The N-4-aminophenyl-N'-propylurea was prepared by sequentially treating commercial 4-nitrophenyl isocyanate with PrNH2 in THF at 20° C. followed by reduction with Na2S2O4 in THF/H2O at 100° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH:6]([N:8]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)C(C)NC1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A solution of 1.07 g (0.005 mole) of (rac)-3-cyclopentylamino-2-methyl-butanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.4 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-butanoic acid ethyl ester (IV-41).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C:19]4([CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[N:18]4[C@@H:13]([C:14](=[O:39])[O:15][C@@H:16]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@H:17]4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:12]3[C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=3[F:47])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:48][CH2:49][CH2:50][C@H:51]([OH:54])[CH2:52][OH:53]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:12]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=4[F:47])[C@H:13]([C:14]([NH:48][CH2:49][CH2:50][C@H:51]([OH:54])[CH2:52][OH:53])=[O:39])[N:18]([C@H:17]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@@H:16]([OH:15])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:19]43[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][CH2:24]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1cccc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Reactant: NCC[C@H](O)CO
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)NCC[C@H](O)CO)[C@H](c1cccc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Yield: 55 %

Procedure:
The compound (1.01 g, 1.51 mmol) obtained in Step 1 of Example 1 and (2S)-4-aminobutane-1,2-diol (WO2007/011162) (475 mg, 4.53 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 1 to give 644 mg (55%) of the title compound as a colorless amorphous solid.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=CC=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[S:92]1[C:96]2[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=2[N:94]=[C:93]1[N:101]([CH2:127][O:128][CH2:129][CH2:130][Si:131]([CH3:134])([CH3:133])[CH3:132])[C:102]([C:104]1[CH:105]=[CH:106][CH:107]=[C:108]2[C:113]=1[CH2:112][N:111]([C:114]1[S:115][C:116]([CH2:123][CH2:124][CH2:125][OH:126])=[C:117]([C:119]([O:121][CH3:122])=[O:120])[N:118]=1)[CH2:110][CH2:109]2)=[O:103].[NH2:135][C:136]1[S:137][CH:138]=[C:139]([C:143]2[CH:148]=[CH:147][C:146](O)=[CH:145][CH:144]=2)[C:140]=1[C:141]#[N:142]>>[NH2:135][C:136]1[S:137][CH:138]=[C:139]([C:143]2[CH:148]=[CH:147][C:146]([O:126][CH2:125][CH2:124][CH2:123][C:116]3[S:115][C:114]([N:111]4[CH2:110][CH2:109][C:108]5[C:113](=[C:104]([C:102](=[O:103])[N:101]([C:93]6[S:92][C:96]7[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=7[N:94]=6)[CH2:127][O:128][CH2:129][CH2:130][Si:131]([CH3:134])([CH3:133])[CH3:132])[CH:105]=[CH:106][CH:107]=5)[CH2:112]4)=[N:118][C:117]=3[C:119]([O:121][CH3:122])=[O:120])=[CH:145][CH:144]=2)[C:140]=1[C:141]#[N:142]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO
Reactant: N#Cc1c(-c2ccc(O)cc2)csc1N
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(-c2csc(N)c2C#N)cc1

Procedure:
Compound 47G was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34B and compound 31F with compound 47F and compound 47C, respectively: MS (ESI(+)): m/z 838 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[F:20][C:2]([F:19])([F:1])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2cccc(C(F)(F)F)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.1 %

Procedure:
Methyl 2-(3-(trifluoromethyl)phenyl)piperidine-4-carboxylate (1.4 g, 4.87 mmol) was dissolved in DCM (50 mL), then DIPEA (2.128 mL, 12.18 mmol) was added. Methyl chloroformate (0.537 mL, 6.82 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 4 h, washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), dried through a phase separator and evaporated yielding dimethyl 2-(3-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (1.7 g, quant.) as an orange oil. MS m/z 346 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([NH:16][NH2:17])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>C1(C)C=CC=CC=1>[C:5]1([C:8]2([C:14]3[N:27]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:17][N:16]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: COC1=NCCCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(C2(c3nnc4n3CCCCCC4)CCCCC2)cc1
Temperature: 120 °C

Procedure:
Anhydrous toluene was added to a mixture of 1-(4-chlorophenyl)cyclohexanecarbohydrazide (62 mg) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (40.1 mg). The reaction vessel was heated to 120° C. overnight, whereupon it was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography to give 3-(1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-α]azocine (2-51) as a white solid.
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]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([C@H:68]([CH3:72])[C:69](O)=[O:70])=[CH:64][CH:63]=1>>[NH2:16][C:14](=[O:15])[C@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:69](=[O:70])[C@H:68]([C:65]2[CH:66]=[CH:67][C:62]([Cl:61])=[CH:63][CH:64]=2)[CH3:72])[C:7]1=[O:12])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=O)[C@@H](c1ccccc1)n1ccc2c(N)cccc2c1=O
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)Nc1cccc2c(=O)n([C@@H](C(N)=O)c3ccccc3)ccc12)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-phenylacetamide (120 mg, 0.00041 mol), N,N-dimethylformamide (1.5 mL, 0.019 mol), N,N-diisopropylethylamine (0.1 mL, 0.0008 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0008 mol) and (S)-2-(4-chlorophenyl)propanoic acid (0.091 g, 0.00049 mol) was allowed to stir over night at room temperature. The solvent was removed and the residue purified by flash chromatography (12 g silica gel, 0-10% MeOH/DCM) and again by preparative HPLC (reverse phase) to obtain the product as an off white solid. MS m/z=460.3 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.95 (s, 1H), 8.13-8.11 (d, J=7.99 Hz, 1H), 8.02 (s, 1H), 7.74-7.72 (d, J=7.60 Hz, 1H), 7.71-7.69 (d, J=8.03 Hz, 1H), 7.55 (s, 1H), 7.50-7.32 (m, 10H), 6.99-6.97 (dd, J=7.89&1.86 Hz, 1H), 6.74 (s, 1H), 6.39-6.37 (d, J=8.02 Hz, 1H), 4.00-3.94 (q, J=6.97 Hz, 1H), 1.44-1.41 (d, J=7.11 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].C(OC(O)C)C>C(OCC)C>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: N=CN
Agent: CCOC(C)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: Oc1ncnc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 130.2 %

Procedure:
2-Amino-4-chloro-benzoic acid (1.00 g, 11.7 mmol, 1.0 eq.), formamidine acetate (3.64 mL, 35.0 mmol, 3 eq.), and ethoxyethanol (20 mL) were refluxed under nitrogen overnight. Cooled to rt. Added 25 mL of diethyl ether. Solids precipitated. Filtered off solids. Pumped under high vacuum to give 2.75 g of white solids as product. LCMS detects (M+H)+=181.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[C:8]=1[C:9]([NH2:11])=[O:10].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:29]([S:31]([NH:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[C:8]=1[C:9]([NH2:11])=[O:10])(=[O:33])=[O:32])[CH3:30]
Reactant: NC(=O)c1c(Nc2ccc(I)cc2F)cc(F)cc1OCc1cccc(N)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1cccc(COc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
In analogy to GP 6b, 89 mg of 2-(3-Amino-benzyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Intermediate 3.2; 0.18 mmol, 1 eq.) were dissolved in 0.75 mL pyridine, treated with 34 μL ethylsulfonyl chloride (0.36 mmol, 2 eq.). and stirred at rt for two days. the resulting mixture diluted with ethyl acetate, washed with water and the organic layers dried. Concentration in vacuo was followed by trituration to provide 84 mg of the desired compound (80% yield) with a melting point of 170° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([O:27]CC)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+].Cl>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylate (810 mg, 2.07 mmol) and lithium hydroxide hydrate (434 mg, 10.3 mmol) in methanol (30 ml) and water (5 ml) was stirred for 18 hours at 25° C. The mixture was adjusted to pH=7 using hydrochloric acid (2molar, 5.15 ml) and then evaporated to dryness under reduced pressure. 1-Methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (1.38 g) as light brown solid was used without further purification. MS: m/z=364.1 (M+H+).