Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]([CH3:14])=[O:13].N1CCCC1>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:14])[O:13][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:3](=[O:4])[CH2:2]1
Reactant: CC(C)=O
Reactant: O=C(CO)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccccc2O1
Yield: 21.6 %

Procedure:
Twenty five grams (25 g) of 2-hydroxyacetophenon, 10.7 g of acetone, and 5.5 g of pyrrolidine were added to 50 ml of toluene, and heated and refluxed. Twenty hours later, the temperature was returned to ambient temperature and the solvent was distilled off under reduced pressure, to which was added 100 ml of 1N hydrogen chloride. The extraction was carried out with 50 ml×3 of chloroform, followed by washing in water, drying over anhydrous magnesium sulfate, filtering off and condensation of the filtered solution. The residue was purified on a silica gel column the fraction containing the purified product were mixed together and the solvent therein was distilled off under reduced pressure to obtain 7 g of 3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-4-one.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[N:9][N:8]=1)C.[ClH:21].[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[OH:32])[CH2:26][CH2:27][NH2:28].C(O)C.Cl>O>[ClH:21].[C:12]1([N:11]2[C:7]([NH:6][CH2:5][CH:4]3[C:29]4[C:25](=[CH:24][C:23]([OH:22])=[C:31]([OH:32])[CH:30]=4)[CH2:26][CH2:27][NH:28]3)=[N:8][N:9]=[N:10]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(CNc1nnnn1-c1ccccc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1cc2c(cc1O)C(CNc1nnnn1-c1ccccc1)NCC2
Yield: 59.7 %

Procedure:
(1-phenyl-1H-tetrazol-5-yl)aminoacetaldehyde diethyl acetal (11 g.) and 3,4-dihydroxyphenethylamine hydrochloride (5.0 g.) were added to a mixture of ethanol (55 ml.) and water (20 ml.), and dissolved with heating and stirring. Conc. hydrochloric acid (6.0 g.) was added thereto and the mixture was refluxed for 8 hours. The reaction mixture was allowed to stand and the precipitated crystals were collected by filtration to give 1-(1-phenyl-1H-tetrazol-5-yl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.9 g.). The crystals were recrystallized from a mixture of isopropyl alcohol and water to give pure crystals (4.2 g.), mp 236° to 241° C (dec.).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1OS(C)(=O)=O.[C:15](#[N:17])C>[C-]#N.C([N+](CC)(CC)CC)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:15]#[N:17]
Reactant: CS(=O)(=O)OC1Cc2ccccc2C1
Reactant: CC#N
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Product: N#CC1Cc2ccccc2C1
Temperature: 55 °C
Yield: 52 %

Procedure:
A mixture of methanesulfonic acid indan-2-yl ester (18.65 g, 87.9 mmol) and tetraethylammonium cyanide (15.10 g) in acetonitrile (180 mL) was heated to 55° C. for 5 hours, cooled and concentrated. The residue was partitioned between ethyl acetate and water, and the organic phase separated. This was dried over MgSO4 and the filtered solution was concentrated and then separated by column chromatography (dichloromethane:ethyl acetate, 6:1-1:1) to give the product as a red solid (6.51 g, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:11]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:36]([O:39][C:40](Cl)=[O:41])([CH3:38])[CH3:37]>C(OCC)(=O)C>[CH:36]([O:39][C:40](=[O:41])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:26]3[CH2:27][CH2:28][CH2:29]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:11]=3)=[CH:4][CH:3]=1)([CH3:38])[CH3:37]
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(OC3CCOCC3)ccc12
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC4CCOCC4)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a mixture of 2-(4-amino-phenyl)-1-cyclobutyl-6-(tetrahydro-pyran-4-yloxy)-1H-indole-3-carbonitrile (897.8 mg, 2.32 mmol), K2CO3 (7 mL), and ethyl acetate (7 mL) was added iPrOCOCl (6.9 mL, 1 M in toluene, 6.96 mmol). The resulting mixture was stirred at room temperature overnight. The organic layer was washed with brine, dried over Mg2SO4, concentrated and purified on silica gel (EtOAc/hexanes, 10% to 30%) to provide the product (1.01 g, 92%) as white solid.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](Br)[SiH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1>CN(C=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([SiH:21]([CH3:23])[CH3:22])[O:4][C:5]2[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=2)=[CH:18][CH:19]=1
Reactant: OCc1ccc(O)cc1
Reactant: C[SiH](C)C(Br)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[SiH](C)C(Oc1ccc(CO)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
Sodium methoxide (4.17 g, 73.4 mmole) was added under argon to a solution of 4-hydroxybenzyl alcohol (8.67 g, 69.9 mmol) in dry DMF (70 mL) and the reaction mixture was stirred for 30 minutes at room temperature. 4-Bromophenyldimethylsilylmethyl-bromide (22.6 g, 73.4 mmol) was added through a canula and the reaction was stirred at RT for 30 minutes and at 65° C. for 45 minutes. The reaction was poured into ice water (250 mL) and extracted with ethyl acetate. The combined extracts were washed with water, 5% sodium bicarbonate and brine and the dried (Na2 SO4). The solution was concentrated to an oil at reduced pressure and purified by flash chromatography (silica gel, 20% ethyl acetate/hexane) to yield the product as a clear, colorless oil (9.23 g, 38%). 1H NMR (400 MHz, CDCl3) 7.48 (dd, 4H), 7.10 (dd, 4H), 4.61 (s, 2H), 3.77 (s, 2H), 0.42 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26]>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[C:25]([NH2:24])=[O:26])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: NC(=O)c1ccccc1B(O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3C(N)=O)cc1OCC2

Procedure:
Following the procedures of Example 475, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 was reacted with (2-aminocarbonylphenyl)boronic acid to give 476. MS (ESI+) 415.2. 1H NMR (400 MHz, DMSO) δ 8.42 (d, J=8.3 Hz, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.54-7.39 (m, 4H), 7.34 (s, 1H), 7.22 (dd, J=8.3, 1.7 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 5.93 (hept, J=6.2 Hz, 1H), 4.55 (q, J=5.7 Hz, 4H), 1.50 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1.[N:15]([O-])=O.[Na+]>CC(O)=O>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:4]2[CH:3]=[C:2]3[CH:1]=[N:15][NH:8][C:7]3=[CH:6][N:5]=2)[CH:10]=1
Reactant: Cc1cc(-c2cccnc2)ncc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: c1cncc(-c2cc3cn[nH]c3cn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
To a solution of 4-methyl-2,3′-bipyridin-5-amine (185 g, 1 mol) in AcOH (27 L) was added aq. NaNO2 solution (82 g, 1.2 mol, 100 mL). The mixture was stirred for 16 h at room temperature. After reaction, the solvent was removed and the residue was purified by silica-gel column chromatography (mobile phase: EA:PE=1:1) to give 5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine as a yellow solid (98 g, 50%)
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([C@@H](C(C)C)C)[N:3]=1.[CH:16]1([NH:19][C:20]([C:22]2[CH:23]=[C:24]([F:32])[C:25]([CH3:31])=[C:26](B(O)O)[CH:27]=2)=[O:21])[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CC(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>[CH:16]1([NH:19][C:20]([C:22]2[CH:23]=[C:24]([F:32])[C:25]([CH3:31])=[C:26]([C:2]3[N:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([CH3:10])[CH:5]([CH3:6])[CH3:4])=[O:7])=[CH:9][CH:10]=3)[CH:27]=2)=[O:21])[CH2:18][CH2:17]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: CC(C)[C@@H](C)c1nc(Cl)ccc1C(N)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)C)cn1
Temperature: 90 °C

Procedure:
6-Chloro-[(R)-(−)-3-methyl-2-butyl]nicotinamide (Intermediate 18, 100 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 6, 100 mg), tetrakis(triphenylphosphine)palladium (10 mg) and aqueous sodium hydrogen carbonate (4 ml) were mixed in propan-2-ol (8 ml) and heated at 90° C. under nitrogen for 18 hrs. The solvents were evaporated from the cooled reaction under vacuum and the residue dissolved as far as possible in ethylacetate. The solution was applied to an SPE (SCX, 10 g) and washed with ethyl acetate. The product was eluted from the column with methanol/0.880 ammonia, and the solvents evaporated in vacuo. The residue was redissolved in ethyl acetate and filtered through an SPE (silica, 0.5 g). The filtrate was reduced to dryness under vacuum and triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-dimethylpropyl]-3-pyridinecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]3[O:13][CH3:14])[C:6]=2[N:7]=1.NC(N)=[S:24]>CCO>[NH2:1][C:2]1[NH:3][C:4](=[S:24])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]3[O:13][CH3:14])[C:6]=2[N:7]=1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Reactant: NC(N)=S
Solvent: CCO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(=S)[nH]c(N)nc21

Procedure:
A solution of the compound from Example 11, Step C (1.5 g, 5 mmol), thiourea (0.4 g, 5.2 mmol.) in abs. EtOH was refluxed for 16 hrs. The solution was evaporated and the resulting oil chromatographed on silica gel (EtOAc/MeOH:9/1) to afford the desired product as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[N:17][CH:18]=1)[CH2:6][CH2:5]2.S(Cl)(Cl)=O.[CH3:27]O>>[CH3:27][O:21][C:20](=[O:22])[CH2:19][C:15]1[CH:16]=[N:17][CH:18]=[C:13]([N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[C:8]2=[O:12])[CH:14]=1
Reactant: O=C(O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 80 °C

Procedure:
To a solution of [5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-acetic acid (example 263 [B]) (217 mg, 0.68 mmol) in methanol (25 mL) was added thionyl chloride (0.44 mL, 6.0 mmol) slowly at 0° C. After the addition, the reaction mixture was warmed up and heated at 80° C. for 2 hours. After cooling back to room temperature, it was concentrated in vacuo and the residue was dissolved in EtOAc (150 mL) and washed with satd. aq. NaHCO3 solution and then brine. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (224 mg, quant.) as light brown oil. MS: 331.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:3]=1[C:4]#[N:5]>CCOCC>[F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(F)c(C#N)c1
Solvent: CCOCC
Product: N#Cc1cc(O)ccc1F

Procedure:
The compound of Preparation 200 was prepared according to the procedure of Preparation 199 substituting the corresponding ether for 2-Fluoro-5-methoxy-benzonitrile. The duration of reaction was between 1 and 24 hours.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11]O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][CH2:11][CH2:10][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCN(CCO)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CCCl)c1ccccc1
Yield: 50 %

Procedure:
2-(N-ethyl-N-phenylamino)ethanol (10 g, 60 mmol) in CH2Cl2 (150 mL) was reacted with SOCl2 (8.8 mL, 121 mmol). The mixture was heated to reflux for one hour and quenched. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide intermediate 15a (5.54 g, 30 mmol, 50%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.28 (m, 2H), 6.74 (m, 3H), 3.65 (m, 4H), 3.46 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H); HRMS (ESI, positive) m/z calcd. for C10H15ClN [M+H]+: 184.0893, found: 184.0836.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Br:18][C:19]1[C:20]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])=[N:21][N:22]([CH3:24])[CH:23]=1.Cl>O.C(O)C>[Br:18][C:19]1[C:20]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH:28][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[N:21][N:22]([CH3:24])[CH:23]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1cc(Br)c(-c2cccc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)c2)n1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)aniline (97 mg, 0.386 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature, extracted with ethyl acetate (50 ml) and washed with water (1×25 ml). The ethyl acetate solution was acidified with aqueous 2N HCl (1×25 ml). The resulting precipitate was collected by filtration, washed with water and isolated as a pale white solid (59 mg, 64%). 1H NMR (DMSO-d6): 10.54 (s, 1H), 9.44 (d, J=2.1 Hz, 1H), 8.75 (dd, J=1.8, 4.8 Hz, 1H), 8.62-8.58 (m, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.65 (t, J=8.3 Hz, 1H), 7.59-7.54 (m, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.19 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]>CC(C)=O>[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(C)=O
Product: O=C(O)C(O)C(O)C(=O)O
Yield: 375 %

Procedure:
In the reaction flask, 10 gm of the oil obtained as per Example 1 was taken in 150 ml of acetone. To this 3.6 gm of L-(+)-tartaric acid was added and mixed at reflux temperature for about 2-3 hours. Acetone was distilled to obtain 13.5 gm of tartaric acid salt of benzyl perindopril.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl>[CH3:8][N:9]([CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CNCc1ccncc1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)N(C)Cc1ccncc1
Yield: 28.2 %

Procedure:
A solution of methyl chlorooxoacetate (2.01 g, 16.37 mmol), N-methyl-N-(4-pyridinylmethyl)amine (2.0 g, 16.37 mmol) and pyridine (1.6 mL, 19.64 mmol) in anhydrous dichloromethane (10 mL) was stirred at 50° C. for 2 h. The mixture was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (40%-100% EtOAc in hexanes) to afford methyl 2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoacetate (77) as a pale yellow oil (0.96 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([F:29])[C:26]([CH2:30][N:31]2[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH2:30][N:31]3[CH2:32][CH2:33][S:34](=[O:38])(=[O:37])[CH2:35][CH2:36]3)=[C:27]([F:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=S1(=O)CCN(Cc2ccc(Cl)nc2F)CC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(CN4CCS(=O)(=O)CC4)c(F)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (25 mg, 0.08 mmol) and 4-[(6-chloro-2-fluoropyridin-3-yl)methyl]thiomorpholine 1,1-dioxide (22 mg, 0.08 mmol) as starting materials.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:17][CH2:18][CH2:19][N:20]1[C:32]2[CH:31]=[CH:30][C:29]3[C:33](=[O:36])[CH2:34][CH2:35][C:28]=3[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2)[CH2:14][CH2:15][CH3:16])(=[O:12])=[O:11])([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[C:41](Cl)([CH3:43])=[O:42]>C1([N+]([O-])=O)C=CC=CC=1.O>[C:41]([C:24]1[CH:23]=[CH:22][C:21]2[N:20]([CH2:19][CH2:18][CH2:17][N:13]([CH2:14][CH2:15][CH3:16])[S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[C:32]3[CH:31]=[CH:30][C:29]4[C:33](=[O:36])[CH2:34][CH2:35][C:28]=4[C:27]=3[C:26]=2[CH:25]=1)(=[O:42])[CH3:43]
Reactant: CC(=O)Cl
Reactant: CCCN(CCCn1c2ccccc2c2c3c(ccc21)C(=O)CC3)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCCN(CCCn1c2ccc(C(C)=O)cc2c2c3c(ccc21)C(=O)CC3)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
Compound 47 (0.638 g, 1.26 mmol) was dissolved in PhNO2 (7 mL). The solution was cooled on an ice bath, AlCl3 (0.67 g, 5.02 mmol) and then AcCl (0.45 mL, 6.31 mmol) were added. The mixture was kept for 40 min (LC/MS monitoring), diluted with water. The product was extracted with CH2Cl2. The extract was evaporated. The residue was evaporated, and the product was passed through Celite, eluent: CH2Cl2-ethyl acetate 100:0→50:50. Yield of 48: 0.453 g (66%).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:12]=2[O:11][CH2:10][C:9]1=[O:13]
Reactant: CCc1cccc2c1OCC(=O)N2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1cccc2c1OCC(=O)N2CCCCl
Yield: 74.9 %

Procedure:
8-Ethyl-4H-benzo[1,4]oxazin-3-one (0.35 g, 2.0 mmol), Cs2CO3 (0.96 g, 2.9 mmol), and 1-chloro-3-iodopropane (0.45 g, 2.2 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.38 g, 74%). Rf=0.64 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 7.01-6.89 (m, 2H), 4.58 (s, 2H), 4.12-4.07 (m, 2H), 3.62 (t, J=6.4 Hz, 2H), 2.65 (q, J=7.6 Hz, 2H), 2.21-2.12 (m, 2H), 1.20 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) d 1.64.9, 143.3, 133.4, 128.4, 124.3, 122.6, 112.6, 67.2, 42.5, 39.2, 30.3, 23.0, 14.5.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:16])[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]=2[CH3:13])[CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[O:27]1CCCC1>CCCCCC>[CH3:13][C:9]1[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]([CH3:16])=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH:1]=[O:27])=[CH:4]2
Reactant: Cc1c(C)c(C)c2cc(C#N)ccc2c1C
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: Cc1c(C)c(C)c2cc(C=O)ccc2c1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under nitrogen atmosphere, 0.8 g of 2-cyano-5,6,7,8-tetramethylnaphthalene was dissolved in 30 ml of tetrahydrofuran, and 5.7 ml of a 1.0M solution of diisobutylaluminum hydride in hexane was added to the resulting solution at 0° C. The resulting mixture was stirred at room temperature for 2.5 hours, quenched with methanol and a saturated aqueous solution of ammonium chloride successively, and extracted with ethyl acetate (50 ml×2) . The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated and the resulting crude product was purified by silica gel column chromatography to give 0.68 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C([OH:20])C.[OH-].[Na+].OO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]23[O:20][CH:8]2[C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11][CH2:12]3)=[CH:16][CH:17]=1
Reactant: CC1(C)CCC(Cc2ccc(Cl)cc2)=CC1=O
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC2(Cc3ccc(Cl)cc3)OC2C1=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1726 g (6.945 mol) crude 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-1-en-3-one obtained as described in (b) above and ethanol (8630 ml) were charged into a 20 liter reactor and warmed to 40° C. to give a clear pale orange solution. The reaction mixture was then cooled to 18° C. and 20% (w/v) sodium hydroxide (650 ml) was added slowly with cooling (ice/water) to maintain this temperature. Keeping the reaction mixture at a temperature between 11° and 20° C., 30% (w/v) aqueous hydrogen peroxide (794 ml, 7 mol) was added over a period of 1 hour and the mixture was then stirred overnight. Water (16 liters) was then added with ice cooling and the reaction mixture stirred for 15 minutes. Centrifugation followed by washing with water (4×21/2 liters) yielded an off-white solid which was then air dried to give 1634 g 1-(4-chlorobenzyl)-1,2-epoxy-4,4-dimethylcyclohexan-3-one, m.pt. 69°-70° C.
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:8][C:7]=1[F:19]>CO>[CH3:1][O:16][C:15](=[O:17])[C:14](=[O:18])[CH:13]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([Br:5])=[C:7]([F:19])[CH:8]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)C(=O)C=Cc1ccc(Br)c(F)c1
Solvent: CO
Product: COC(=O)C(=O)C=Cc1ccc(Br)c(F)c1
Yield: 32.7 %

Procedure:
Acetyl chloride (2.9 mL, 41.0 mmol) was slowly added at 0° C. to methanol (15.0 mL) under stirring. A solution of 4-(4-bromo-3-fluoro-phenyl)-2-oxo-3-butenoic acid (3.2 g, 11.7 mmol) prepared in Step 1 in methanol (5.0 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 1 hour, additionally at 80° C. for 16 hours, and then filtered at room temperature to give 1.1 g of the titled compound as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[K+].[I:15]I>CN(C=O)C>[I:15][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1
Reactant: II
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25.0 g (154.2 mmol) 5-nitroindole (Aldrich N1, 760-2) and 21.7 g (386.7 mmol) potassium hydroxide were dissolved in 270 ml DMF. To this solution 39.5 g (155.6 mmol) iodine dissolved in 250 ml DMF were added drop wise during one hour. The resulting mixture was subsequently stirred for 1.0 h at room temperature. Afterwards the reaction mixture was poured on 2.5 l of sludge. The formed precipitate was collected by filtration and washed twice with water. The residue obtained was dried in a vacuum (yield: 43.0 g).