Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](N(C)C)=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(O)(=[O:25])C.Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Into a 200 ml four-necked flask equipped with a thermometer, a stirrer and a reflux condenser, 15.5 g (50 mmol) of 1-(4-fluorophenyl)-2-(4-trifluoromethylphenyl)-N,N-dimethylethenylamine, 80 ml of acetic acid and 30 ml of concentrated hydrochloric acid were charged and reacted with stirring for two hours under refluxing under heating by an oil bath. After completion of reaction, 500 ml of water was added, and precipitated crystals were collected by filtration and washed with a 2% sodium hydrogen carbonate aqueous solution and water. Then, the crystals were further washed and purified with 20 ml of n-hexane and then vacuum-dried to obtain 12.7 g (yield: 90.3%) of the desired compound (melting point: 93-95° C.) as slightly yellow crystals.
Reaction SMILES: C[O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:17])[N:10]2[CH2:13][C@@H:14]2[CH2:16][O:15]2)=[CH:5][CH:4]=1>CN(C=O)C>[OH:15][CH2:16][C@H:14]1[N:12]2[C:11]3[N:10]([C:9](=[O:17])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]2=[O:2])[CH2:13]1
Reactant: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CC2
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Yield: 30.9 %

Procedure:
A solution of 7-(methyloxy)-1-[(2R)-2-oxiranylmethyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one (1.167 g, 4.98 mmol) in DMF (20 ml) under argon was heated to 120° C. for 6 h. Reaction was then evaporated and chromatographed (0-20% MeOH/DCM) to give product as an orange solid (339 mg, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Br)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
tert-Butyl 4-(2-bromo-4-nitrophenoxy)piperidine-1-carboxylate (12.21 mmol, 4.9 g) was dissolved in dichloromethane (40 mL) and trifluoroacetic acid (73.3 mmol, 8.35 g) added. The mixture was stirred at room temperature for 3 hours before concentrating under reduced pressure. The resulting residue was dissolved in dichloromethane (150 mL) and washed with a saturated solution of sodium bicarbonate (3×50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (3.3 g).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:9]([N:16]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=2[CH:18]=[C:17]1[CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.CN([CH:31]=[O:32])C>>[CH3:1][O:4][C:31](=[O:32])[CH:12]([O:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[CH:18]=[C:17]([CH3:26])[N:16]2[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:11][CH:10]([CH3:15])[CH3:9]
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(CC(C)C)Oc1cccc2c1cc(C)n2Cc1ccccc1
Temperature: 70 °C

Procedure:
To a stirred suspension of K2CO3 (0.563 g, 4.22 mmol), NaI (0.031 g, 0.21 mmol) and 1-benzyl-2-methyl-1H-indol-4-ol (1) (0.500 g, 2.11 mmol) in dry DMF (15 mL), a solution of (CH3)2CHCH2BrCHCO2Me (0.66 g, 3.2 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was heated at 70° C. for 7 h, cooled to room temperature and water (30 mL) was added. The mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over Na2SO4 and evaporated. Flash chromatography of the residue over silica gel, using 10% EtOAc in hexanes to 20% EtOAc in hexanes, gave product 2 as a pale yellow solid. Yield: 0.54 g (70%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[C:17]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[CH:9][CH:10]=1)=[O:18]
Reactant: CCOc1ccccc1
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(I)ccc2Cl)cc1
Temperature: 6 °C
Reaction time: 2 h

Procedure:
A jacketed 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with aluminum chloride (97.68 g, 0.733 mol, 1.04 equiv), dichloromethane (0.65 L, KF=0.003 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 6° C. Then ethoxybenzene (90 mL, 0.712 mol, 1.01 equiv) was added over 7 minutes keeping internal temperature below 9° C. The resulting orange solution was diluted with dichloromethane (75 mL) and was cooled to −7° C. Then a solution of 2-chloro-5-iodobenzoyl chloride (<0.706 mol) in 350 mL dichloromethane was added over 13 minutes keeping the internal temperature below +3° C. The reaction mixture was warmed slightly and held at +5° C. for 2 hours. HPLC analysis suggested the reaction was complete and the reaction was quenched into 450 mL pre-cooled (˜5° C.) 2N aq. HCl with stirring in a jacketed round bottom flask. This quench was done in portions over 10 min with internal temperature remaining below 28° C. The quenched biphasic mixture was stirred at 20° C. for 45 min and the lower organic phase was washed with 1 N aq. HCl (200 mL), twice with saturated aq. sodium bicarbonate (200 mL per wash), and with saturated aq. sodium chloride (200 mL). The washed extract was concentrated on a rotary evaporator to afford crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone as an off-white solid (268.93 g, 99.0 area % by HPLC at 220 nm, 1.0 area % regioisomer at 200 nm, 98.5% “as-is” yield).
Reaction SMILES: C(OC([N:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)[NH2:9])=O)(C)(C)C.O1CCOCC1.[ClH:24]>C(Cl)Cl>[ClH:24].[NH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)N(N)c1ccc(C#N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc(NN)cc1

Procedure:
Title compound 52A, N-(4-cyano-phenyl)-hydrazinecarboxylic acid tert-butyl ester (0.23 g, 1.0 eq, 0.99 mmol) was suspended in a mixture of 4M HCl in Dioxane (4.2 ml, 17.0 eq, 16.8 mmol) and DCM (5 ml). The mixture was then stirred at room temperature for 18 hours The resultant precipitate was isolated by filtration and washed with DCM to yield the title compound as a cream solid. (0.14 g, 0.8 mmol, 85%). 1H NMR (DMSO) 400 MHz: Indicates product in >95% purity
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Al+3].[CH3:6][CH:7]([CH3:9])[O-].[CH3:10][CH:11]([CH3:13])[O-].[C:14]1([CH3:20])[CH:19]=[CH:18]C=C[CH:15]=1>>[CH3:6][C:7]1([CH3:9])[C:13]2[CH2:11][CH2:10][CH2:4][CH:2]([OH:3])[C:1]=2[C:14]([CH3:15])([CH3:20])[CH:19]1[CH3:18]
Reactant: CC(C)[O-]
Reactant: Cc1ccccc1
Agent: [Al+3]
Product: CC1C(C)(C)C2=C(C(O)CCC2)C1(C)C
Reaction time: 8 h

Procedure:
Into a 2-liter reaction vessel are placed 831 ml of toluene and 226.9 grams (1.11 moles) of aluminum isopropoxide. The mixture is heated to reflux and while refluxing, over a one hour period, tetrahydro pentamethylindane epoxide having the structure: ##STR62## is added to the reaction mass. The reaction mass is continued to be refluxed for a period of twelve hours while being monitored by GLC analysis. An additional 0.5 moles of aluminum isopropoxide is added (101.5 grams) at the end of the twelve hour period and the refluxing is continued for an additional eight hours. At the end of the twenty hour period, an additional 50.7 grams of aluminum triisopropylate is added and the reaction mass is continued to be refluxed for an additional twenty two hours (total reflux time 42 hours).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[Br:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>C(OCC)(=O)C>[Br-:28].[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][CH:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:16][CH2:15][N+:14]([CH2:29][C:30](=[O:31])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([CH2:19][CH2:18]3)[CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccc(F)cc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(NCc1ccc(F)cc1)c1ccccc1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
A mixture of (R)-quinuclidin-3-yl 2-(4-fluorobenzylamino)-2-phenylacetate (C78) (61 mg, 0.17 mmol) and 2-bromo-1-phenylethanone (33.0 mg, 0.17 mmol) in ethyl acetate (3 mL) is stirred at RT overnight. The solid is collected by suction filtration and washed with Et2O. The product is further purified by flash chromatography (DCM/MeOH=95/5 to 92/8) to obtain the title compound as a white solid (35 mg, 37% yield, bromide salt, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15]C(O)=O)\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21].S(Cl)(Cl)=O.CN(C)C=[O:31].Cl[CH2:34][Cl:35]>>[OH:19][C:5]1[C:6]([CH:10]([CH2:11]/[C:12](/[CH3:13])=[CH:14]/[CH3:15])[C:34]([Cl:35])=[O:31])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[C:3]2[C:4]=1[C:20](=[O:21])[O:22][CH2:23]2
Reactant: ClCCl
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: C/C=C(\C)CC(C(=O)Cl)c1c(O)c2c(c(C)c1OC)COC2=O

Procedure:
A solution of 500 mgs of mycophenolic acid in 10 ml of dichloromethane containing 0.5 ml of thionyl chloride and 0.05 ml of N.N-dimethylformamide was maintained at 25° C. for 3 hours. The volatile components were then distilled off under vacuum to obtain crude (E)-[1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl]-4-methyl-4-hexenoyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]([F:23])([F:22])[F:21])[C:14]=1[F:24].[CH:27]([Sn](CCCC)(CCCC)CCCC)=[CH2:28].CCOC(C)=O.[Na+].[Cl-]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]([CH3:26])[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:27]=[CH2:28])=[C:15]([C:20]([F:23])([F:22])[F:21])[C:14]=1[F:24]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(Nc2ccc(Br)c(C(F)(F)F)c2F)c(CC(=O)N(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc(Nc2ccc(C)cc2CC(=O)N(C)C)c(F)c1C(F)(F)F
Temperature: 120 °C

Procedure:
5-Methyl-2-(2′-fluoro-4′-bromo-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide prepared by method outlined in example 3 (0.8 g, 1.7 mmol), Pd(PPh3)4 (0.1 g, 0.09 mmol), and vinyl tributylstannane (0.6 g, 1.9 mmol) in DMF (5 mL) is heated to 120° C. under nitrogen overnight. After cooling, the reaction is portioned between EtOAc and saturated aqueous solution of NaCl. The separated organic layer is washed twice with fresh saturated aqueous solution of NaCl. The EtOAc layer is dried and concentrated under reduced pressure. The residue is purified by flash chromatography to give 5-Methyl-2-(2′-fluor-4′-vinyl-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([NH2:12])[C:2]=12.[CH3:13][CH2:14][O:15]C(C)=O.O(C(C)C)C(C)C.[NH4+].[OH-]>C(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]([NH:12][C:14](=[O:15])[CH3:13])[C:2]=12
Reactant: NC1CCCCc2cccnc21
Reactant: CCOC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H]1CCCCc2cccnc21
Reaction time: 24 h

Procedure:
Following the general procedure, 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine (195 mg, 1.20 mmol), CALB (59 mg), EtOAc (0.48 mL) and iPr2O (4.6 mL) were stirred for 24 hours. The conversion determined from 1H NMR by integration of the peaks at 5.05 ppm (CHNHAc) and 4.34 ppm (CHNH2) was 58%. Flash chromatography of the material on silica gel using 1:10 MeOH:CH2Cl2 followed by 1:1:4 NH4OH:MeOH:CH2Cl2 furnished the (R)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetamide ((134 mg, 55%) in 45% ee (chiral GC method: 180° C. for 15 min, ramp rate of 10° C./min to 210° C., hold 10 min, (S)-(−)-enantiomerrt=17.4 min, (R)-(+)-enantiomerrt=17.1 min); [α]D=−10° (c 1.34, CHCl3); 1H NMR (CDCl3, 300 MHz) δ1.09-1.31 (m, 2H), 1.80-2.03 (m, 3H), 2.06 (s, 3H), 2.24 (d, 1H, J=13.5 Hz), 2.65-2.71 (m, 1H), 2.75-2.85 (m, 1H), 4.96-5.01 (m, 1H), 7.06 (dd, 1H, J=7.0, 4.8 Hz), 7.38 (d, 1H, J=7.0 Hz), 8.11 (br s, 1H), 8.28 (d, 1H, J=4.8 Hz); 13C NMR (CDCl3) δ 24.0, 27.3, 30.1, 34.5, 34.8, 53.8, 122.8, 137.0, 137.5, 145.5, 159.2, 169.6; MS m/z: 205 (M+H+). The unreacted (S)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine (was isolated in 41% yield (81 mg) and 61% ee (chiral GC, (S)-enantiomerrt=5.81 min, (R)-enantiomerrt=6.00 min); [α]D=+2° (c 1.13, CHCl3); and displayed spectra identical to the starting material: 1H NMR (CDCl3, 300 MHz) δ 1.20-1.35 (m, 1H), 1.36-1.53 (m, 1H), 1.75-2.01 (m, 4H), 2.15 (br s, 2H), 2.69-2.77 (m, 2H), 4.16 (d, 1H, J=8.7 Hz), 6.95-7.06 (m, 1H), 7.32 (d, 1H, J=6.0 Hz), 8.34 (br s, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[CH2:11][CH2:12][CH:13]([NH:17][CH3:18])[CH2:14][CH:15](O)[C:9]=2[CH:8]=1.O.[OH-].[Na+]>O1CCOCC1>[ClH:6].[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[CH2:11][CH2:12][CH:13]([NH:17][CH3:18])[CH:14]=[CH:15][C:9]=2[CH:8]=1
Reactant: CNC1CCc2ccc(Cl)cc2C(O)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CNC1C=Cc2cc(Cl)ccc2CC1
Product: Cl
Temperature: 20 °C
Yield: 164.9 %

Procedure:
7.4 ml of concentrated sulfuric acid were added to a refluxing solution of 3.7 g of 3-chloro-5ξ-hydroxy-7-methylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene in 37 ml of dioxane and the mixture was refluxed for 20 minutes and then was cooled to 20° C. 50 ml of water were added to the reaction mixture which was then made alkaline with sodium hydroxide. The mixture was extracted with methylene chloride and the organic extracts were washed with water, dried and evaporated to dryness. The resulting 3.5 g of product were dissolved in 5 ml of ethyl acetate and a solution of ethyl acetate saturated with hydrogen chloride was added thereto at 10° C. The mixture was vacuum filtered to obtain 3.3 g of 2-chloro-7-methylamino-6,7-dihydro [5H] benzocycloheptene hydrochloride melting at 195° C which was identical to the product of Example 10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:32][CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].C1C=C(Cl)C=C(C(OO)=[O:43])C=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:32]([CH3:33])=[O:43])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(SC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (600 mg, 1.24 mmol) in CH2Cl2 (15 mL) was added m-CPBA (293 mg, 1.31 mmol). The mixture was stirred at room temperature for 10 minutes, then directly loaded onto a column. CombiFlash chromatography (mobile phase EtOAc/Hexane) afforded the title compound as a white solid 475 mg (77%). LC-MS m/z 500 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:17]1CCCC1>[Fe]>[F:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=[O:17])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=C(C)[N+](=O)[O-])cc1F
Reactant: C1CCOC1
Agent: [Fe]
Agent: Cl
Product: COc1ccc(CC(C)=O)cc1F

Procedure:
Concentrated hydrochloric acid (30 ml) was added dropwise, over 45 minutes, to a stirred mixture of iron powder (6 g) and 1-(3-fluoro-4-methoxyphenyl)-2-nitroprop-1-ene (5.7 g) in tetrahydrofuran (100 ml) at reflux. The mixture was heated under reflux for a further two hours, cooled, filtered and evaporated. Water (100 ml) was added to the residue and extracted with dichloromethane. The dried (magnesium sulphate) extracts were evaporated to dryness to give the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH2:2]1.[Cl:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH3:35]>>[ClH:23].[CH3:35][C:26]1[CH:27]=[CH:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[CH2:24][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH2:2]1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)CC2
Reactant: Cc1ccc2ccccc2c1CCl
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(Cc3c(C)ccc4ccccc34)C1)CC2
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloromethyl-2-methyl-naphthalene analogously to Example 1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]([NH2:14])=[S:13]>CO>[C:5]1([C:3]2[N:11]=[C:12]([NH2:14])[S:13][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(N)=S
Solvent: CO
Product: Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
2-Bromo-1-phenyl-ethanone (19.9 g, 0.100 mol) and thiourea (7.9 g, 0.10 mol) were mixed in a 150 mL of methanol. The reaction mixture was warmed to dissolve the reagents and then allowed to stir overnight at room temperature. The methanol was evaporated to dryness and the crude product was dissolved in a minimum of ethyl acetate. The crude product was then extracted twice with 1M sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the pure product (16.8 g, 0.0953 mol, 95.3%) of product. ESI-MS m/z calc. 176.0, found 177.2 (M+1)+ Retention time 1.41 minutes. 1H NMR (400 MHz, CD3CN) δ 5.73 (s, 2H), 6.87 (s, 1H), 7.28-7.34 (m, 1H), 7.36-7.43 (m, 2H), 7.79-7.85 (m, 2H).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[NH:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:30]([CH2:38][CH2:39]Br)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C(#N)C>[N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:39][CH2:38][CH:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(NNC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
Bis(phenylmethyl) 1,2-hydrazinedicarboxylate (5.91 g, 19.68 mmol) was placed in a 500 ml round bottomed flask and acetonitrile (150 ml) was added followed by cesium carbonate (14.11 g, 43.3 mmol). 1,1-Dimethylethyl 2,4-dibromobutanoate (4.00 ml, 19.68 mmol) was added dropwise and the reaction was heated to 60° C. and stirred overnight. The resulting solution was cooled to room temperature and passed through a pad of celite. The filtrate was concentrated and purified via combiflash silica gel chromatography (0-100% EtOAC in hex) yielding 3-(1,1-dimethylethyl) 1,2-bis(phenylmethyl) 1,2,3-pyrazolidinetricarboxylate (5.3 g, 12.03 mmol, 61.1% yield) as a pale yellow oil.
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH2:28]([N:30]=C=S)[CH3:29].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:28]([NH:30][C:2]1[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[CH:8][N:7]=[C:6]([C:11]1[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=13)[N:5]=2)[CH3:29]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Reactant: CCN=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNc1nc2cnc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in CH2Cl2 (2 mL), ethyl isothiocyanate (0.042 ml, 0.48 mmol), EDC.HCl (171 mg, 0.89 mmol) and DIPEA (0.25 ml, 1.49 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 80° C. and 150 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 42 mg of the desired compound (36% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[N:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[N:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1)[CH3:43]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2cnnn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2cnnn12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (470 mg), rhodium(II) acetate (dimer) (22 mg) and methylene chloride (10 mL) was added dropwise ethyl diazoacetate (137 mg) under an argon atmosphere, and the mixture was stirred at room temperature for 3 days. The reaction mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→20/80 (volume ratio)] to give the title compound as a colorless amorphous compound (203 mg, 37%).