Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([Cl:11])[CH:3]=1.[NH:12]([C:14](=[S:16])[NH2:15])[NH2:13].O=P(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:16][C:14]([NH2:15])=[N:12][N:13]=2)=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: NNC(N)=S
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(-c2ccc(Br)cc2Cl)s1
Temperature: 78 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
A stirred mixture of 4-bromo-2-chlorobenzoic acid (2 g, 8.49 mmol) and hydrazinecarbothioamide (1.161 g, 12.74 mmol) was cooled under nitrogen in an ice-bath. POCl3 (2.375 mL, 25.5 mmol) was then added dropwise. On completion of addition, the reaction mixture was warmed to 78° C. and left to stir for 3 hours. The reaction mixture was allowed to cool to room temperature then cooled further in an ice-bath. Quenching by addition of ice-water (50 mL) resulted in a solid/gum-like mass. This material was sonicated for 1.5 hours and the resulting suspension was diluted with a further 50 mL water and slurried for 16 hours. The suspension was filtered under vacuum and the solid rinsed with water, then re-suspended in saturated NaHCO3(aq) (100 mL). The suspension was slurried for 30 minutes then filtered under vacuum and rinsed with water to afford the crude product as an off-white solid. The crude product was pre-absorbed onto silica gel and purified by flash chromatography using a gradient from 0-10% MeOH/DCM over 30 minutes to afford the title compound as a pale yellow/off-white solid (1.087 g, 44% yield). LC-MS: Rt 1.09 min; MS m/z 292.0 [M+2H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J=8.59 Hz, 1H), 7.91 (d, J=2.02 Hz, 1H), 7.68 (dd, J=8.59, 2.02 Hz, 1H), 7.51 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[I:28]I>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[I:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccncc1I
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
To a solution of pyridin-4-yl-carbamic acid tert-butyl ester (14.8 g, 76.3 mmol) (reference example 44b) in THF (300 mL) is added N,N,N′,N′-tetramethylethylene-diamine (34.5 mL, 230 mmol) and the solution cooled to −78° C. To this solution is added slowly (2.5M) n-butyllithium (91.5 mL, 230 mmol), the reaction temperature allowed to rise to −20° C. and the resulting mixture stirred for 1.5 hours. The mixture is cooled to −78° C. and a solution of iodine (29.04 g, 114 mmol) in THF (60 mL) is added then stirred for 10 min. The mixture is warmed to 20° C., stirred 30 min then diluted with ethyl acetate, washed with water, sat. sodium thiosulfate and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 20% ethyl acetate in hexanes) to give 17.7 g of title compound as a light yellow crystalline solid. 1H NMR (CDCl3) δ 1.54 (s, 9H), 7.03 (bs, 1H), 8.10 (d, J=6 Hz, 1H), 8.34 (d, J=6 Hz, 1H), 8.74 (s, 1H). MS (EI) m/z 320 (M+).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccs2)c1Br
Yield: 34 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-thiophenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-thiophenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 125°-127° C., yield 34%.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6](=O)[NH:7][C:8]=1[CH3:9])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>O>[Cl:15][C:6]1[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]([CH2:1][CH3:2])=[C:8]([CH3:9])[N:7]=1
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: CCc1cc([N+](=O)[O-])c(Cl)nc1C
Yield: 57.5 %

Procedure:
A mixture of 5-ethyl-6-methyl-3-nitro-2-(1H)-pyridinone (2.38 g, 13 mmol) and phosphorus pentachloride (3.3 g, 15.6 mmol) was heated under an atmosphere of nitrogen at 140°-150° C. for 15 minutes. The resultant brown oil was then treated with water and the product extracted into chloroform. The organic extract was washed three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (15 torr). The residue was passed through a small plug of silica gel, eluted with 2% methanol in chloroform. Collection and concentration of appropriate fractions yielded 1.5 g (57.5%) of the corresponding chloropyridine as a clear pale brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH:4]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]1=[O:19].[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH:4]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:3]1=[O:19]
Reactant: [H][H]
Reactant: CC(C)CC1C(=O)N(C)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC1NCCN(C)C1=O

Procedure:
1-Methyl-3-(2-methylpropyl)-4-(phenylmethyl)piperazinone (Example 47, 2.1 g.) is dissolved in methanol (200 ml.), 10% palladium charcoal (1.0 g.) is added and the product is hydrogenated (50 lb. initial hydrogen pressure until the uptake of hydrogen ceased. The solution is filtered and the methanol is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)([C:10]#[C:11][CH:12]([OH:14])[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(OC)(C)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10]#[C:11][CH:12]([O:14][C:22](=[O:24])[CH3:23])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=CCCC(C)(C)C1(O)C#CC(C)O
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CC(=O)OC(C)C#CC1=C(C)C=CCC1(C)C
Temperature: 25 °C
Reaction time: 27 h
Yield: 45 %

Procedure:
In a 500 ml. three-necked flask fitted with a mechanical stirrer, a dropping funnel, a thermometer and a reflux condenser protected by a calcium chloride tube is placed a mixture of 66 g. of 2,6,6-trimethyl-1-hydroxy-1-(3-hydroxy-but-1-ynyl)cyclohex-2-ene and 76 g. of pyridine in 200 ml. of tertiary butylmethyl ether. To the stirred solution is added 34 g. of acetic anhydride at room temperature. The reaction mixture is stirred for a period of 27 hours at ambient temperature. The reaction mixture is then poured into 200 ml. of water and the organic layer is separated, washed with 10% hydrochloric acid, subsequently with water, 10% sodium bicarbonate solution and water, and finally dried over sodium sulfate. Concentration yields a residue which gives on distillation 33 g. or 45% yield of 2,6,6-trimethyl-1-(3-acetoxy-but-1-ynyl)cyclohexa-1,3-diene, b.p. 125° C./1 mm., nD20 1.5045.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[CH:8]([CH3:13])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:22][C@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@@H:23]2[CH3:22])[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[CH:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: CC1c2nc(Cl)nc(Cl)c2CS1(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2CS1(=O)=O
Yield: 39.7 %

Procedure:
To a solution of 2,4-dichloro-7-methyl-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (160 mg, 0.63 mmol), and triethylamine (64 mg, 0.63 mmol) in DMF (3 mL) at 0° C. was added 3-(S)-methylmorpholine (57 mg, 0.57 mmol). The resultant mixture was stirred at rt for 2 h. The solvent was removed under vacuum and the residue obtained partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give the product which was purified by preparative TLC (petroleum ether/ethyl acetate=2/1) to produce 2-chloro-7-methyl-4-[(3S)-3-methylmorpholin-4-yl]-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (72 mg, 36% yield).
Reaction SMILES: CS(C)=O.C(=O)=O.CC(C)=O.C(Cl)(=O)C(Cl)=O.[C:18]([O:22][C:23](=[O:40])[NH:24][C@H:25]1[CH2:30][CH:29]([OH:31])[CH2:28][S:27][C@@H:26]1[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:18]([O:22][C:23](=[O:40])[NH:24][C@H:25]1[CH2:30][C:29](=[O:31])[CH2:28][S:27][C@@H:26]1[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(O)CS[C@@H]1c1cc(F)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)CS[C@@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
DMSO (503 μL, 7.09 mmol) was added to a dry ice/acetone cooled solution of oxalyl chloride (253 μL, 2.84 mmol) in methylene chloride (5.0 mL). After 2 min, a solution of tert-butyl[(2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-thiopyran-3-yl]carbamate (490 mg, 1.42 mmol) in methylene chloride (5.0 mL) was added and the mixture was stirred for 30 min. Triethylamine (1.98 mL, 14.2 mmol) was added and the solution was stirred for 10 min and then removed from the dry ice/acetone bath and warmed to room temperature. Methylene chloride (50 mL) and water (30 mL) were added and the organic phase was dried with sodium sulfate, filtered and evaporated to an oil. The residue was placed onto preparative tlc plates, developed with 1:2 EtOAc/hexanes and eluted with EtOAc to give the title compound as a solid. The mixture was resolved by preparative HPLC Chiralpak AD chromatography eluting with 25% IPA/heptane to give the first eluting isomer, namely, tert-butyl[(2S,3R)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-thiopyran-3-yl]carbamate and the second eluting title compound isomer, namely, tert-butyl[(2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-thiopyran-3-yl]carbamate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[NH:13][CH:14]=[CH:15][N:16]=3)[S:7][C:6]=2[CH:17]=1.O.[CH3:19][N:20](C)C=O>>[NH:16]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:11][C:8]1[S:7][C:6]2[CH:17]=[C:2]([C:19]#[N:20])[CH:3]=[CH:4][C:5]=2[C:9]=1[CH3:10]
Reactant: CN(C)C=O
Reactant: Cc1c(Cc2ncc[nH]2)sc2cc(Br)ccc12
Solvent: O
Product: Cc1c(Cc2ncc[nH]2)sc2cc(C#N)ccc12

Procedure:
A mixture of 6-bromo-2-(1-imidazolylmethyl)-3-methylbenzo[b]-thiophene (1.01 g) and cuprous cyanide (1.80 g) in N,N-dimethylformamide (20 ml) was heated under reflux for 22 hours and then cooled and poured into water. The solid was filtered off, washed with water and then suspended in a mixture of concentrated aqueous ammonia solution (100 ml) and ethyl acetate (150 ml) and the mixture was stirred until no solid remained. The organic layer was separated, washed with water, dried (Na2SO4) and evaporated. The residue was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-6-carbonitrile (0.58 g), m.p. 154°-155°.
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:4]([SH:3])[CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
S-(5Z,8Z,11Z,14Z,17Z)-Icosa-5,8,11,14,17-pentaenyl ethanethioate (7.00 g, 20.2 mmol) was dissolved in MeOH (100 mL) by stirring 10 minutes until the droplets of oil dissolved, before anhydrous potassium carbonate, K2CO3 (2.79 g, 20.2 mmol) was added in one portion. The mixture was stirred for 1 hour and 20 minutes at ambient temperature and quenched by addition of 1 M HCl (50 mL) and water (150 mL). The white cloudy mixture was added Et2O (250 mL) and the phases were separated. The water phase was extracted with Et2O (2×250 mL). The combined organic phases were washed with brine (250 mL) and dried (MgSO4). Filtration and evaporation gave the title compound as oil (5.99 g, 97% yield), which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[N:49]=[C:48]([CH3:50])[O:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:49]=[C:48]([CH3:50])[O:47][N:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Cc1nc(CCl)no1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)no1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole and isolated as yellow gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:15][CH3:16])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[K+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:15][CH3:16])[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(CC)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(CC(=O)O)c1ccc(F)cc1
Yield: 83.1 %

Procedure:
This compound was prepared in an analogous manner to Example 18c with the replacement of 3-(4-fluorophenyl)butyrate with ethyl 3-(4-fluorophenyl)valerate (38.95 g 0.144 mol, containing 29% triethyl phosphoneacetate) and using an excess of 85% potassium hydroxide (18.05 g, 0.273 mol, Mallinckrodt). The dichloromethane layers were combined, washed with deionized water (50 ml) and concentrated by spin evaporation in vacuo. The residue was crystallized from hexanes to give 23.47 g (83%) of 3-(4-fluorophenyl)valeric acid as a white crystalline solid: NMR (DMSO-d6): d 12 (s, 1H), 7.28-7.24 (m, 2H), 7.14-7.08 (m, 2H), 2.91-2.89 (m, 1H), 2.64-2.41 (m, 2H), 1.66-162 (m, 1H), 1.56-1.51 (m, 1H), 0.71 (t, 3H, J=7.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:13][CH:10]1[CH2:12][CH2:11]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: NC1CC1
Product: Clc1cccc(CNC2CC2)c1

Procedure:
Synthesized according to typical procedure J from 3-chlorobenzaldehyde and cyclopropylamine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[NH:23])[N:20]([OH:22])[CH3:21])[C:3]=1[S:24]([C:26]([F:29])([F:28])[F:27])=[O:25].[CH2:30]=O>C(#N)C.C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]2[N:20]([CH3:21])[O:22][CH2:30][N:23]=2)[C:3]=1[S:24]([C:26]([F:28])([F:29])[F:27])=[O:25]
Reactant: C=O
Reactant: CN(O)C(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1OCN=C1c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 5 h
Yield: 25.1 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(N-hydroxy-N-methylamidino)-4-trifluoromethylsulfinylpyrazole(1.00 g, 2.07 mmol) was dissolved in 10 ml of acetonitrile, and then aqueous 37% formaldehyde solution 840 mg (10.3 mmol) and 5 drops of acetic acid were added. After the mixture was stirred at 50° C. for 5 hours, aqueous 37% formaldehyde solution 840 mg (10.3 mmol) and, 5 drops of acetic acid were further added, followed by stirring at 50° C. for 5 hours. The reaction mixture was concentrated in vacuo and to the residual oil was added ethyl acetate, and then washed twice with an aqueous saturated sodium hydrogencarbonate solution, once with an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The resulting concentrated residue was purified by silica gel column chromatography [eluent: mixed solvent of ethyl acetate and n-hexane (volume ratio=1:2)] to obtain 260 mg (0.52 mmol) of the title compound as a colorless crystal. Yield 25%.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[O:8]=[C:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](CCO)=[CH:14][CH:13]=1.O1CCCC1>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9](=[O:8])[CH3:21])=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)COc1ccc(CCO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)COc1ccc(CCOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1.96 g of acetic anhydride were added, whilst ice-cooling, to a mixture of 3.1 g of 2-[4-(2-oxopropoxy)phenyl]ethanol (prepared as described in Preparation 7), 50 ml of anhydrous tetrahydrofuran and 2.53 g of pyridine, and the resulting mixture was stirred at room temperature for 3.5 hours. At the end of this time, 12.5 g of pyridine and 9.8 g of acetic anhydride were added, whilst ice-cooling, and the mixture was allowed to stand at room temperature for 1 day, after which the solvent was removed by distillation under reduced pressure, and the residue was mixed with water and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give the title compound having an Rf=0.71 (thin layer chromatography over silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].Cl[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1>>[CH3:1][C:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)=[CH:14][CH:15]=1)([CH3:8])[C:3]([OH:5])=[O:4]
Reactant: Clc1cnccn1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2cnccn2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate and chloropyrazine.
Reaction SMILES: CS(C)=O.Cl.[NH2:6][OH:7].C(N(CC)CC)C.[O:15]=[S:16]1(=[O:36])[C:22]2[CH:23]=[C:24]([O:27][C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[C:31]#[N:32])[CH:25]=[CH:26][C:21]=2[NH:20][CH2:19][CH2:18][NH:17]1>C(OCC)C.ClCCl.O.C1COCC1>[O:36]=[S:16]1(=[O:15])[C:22]2[CH:23]=[C:24]([O:27][C:28]3[CH:29]=[C:30]([C:31](=[N:6][OH:7])[NH2:32])[CH:33]=[CH:34][CH:35]=3)[CH:25]=[CH:26][C:21]=2[NH:20][CH2:19][CH2:18][NH:17]1
Reactant: NO
Reactant: N#Cc1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCN3)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCN3)c1
Reaction time: 0.42 h

Procedure:
To 750 μl of DMSO there are added hydroxylamine hydrochloride (1.90 mmol) and then triethylamine (1.90 mmol). An abundant white precipitate is formed, which is diluted by adding 3 ml of THF and stirring is carried out for 25 minutes at ambient temperature. The THF is evaporated off under reduced pressure and the suspension is filtered. The product of Example 6 (0.317 mmol) is added to the filtrate and the solution is stirred overnight at ambient temperature. After adding water to the reaction mixture, a gum forms which is made solid by adding dichloromethane and ethyl ether. The solid is filtered off and rinsed with water and ethyl ether to yield the title product.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: C[C@@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)NC(=O)CO
Reactant: ClCc1ccccn1
Agent: Cl
Product: C[C@@H](COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)NC(=O)CO
Yield: 57 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxyacetamide to give the title compound in 57% yield; NMR spectrum (DMSO-d6) 1.23 (d, 3H), 3.64-3.81 (m, 2H), 4.24-4.36 (m, 2H), 4.45-4.59 (m, 1H), 5.29 (s, 2H), 5.45 (t, 1H), 7.13-7.23 (m, 2H), 7.35 (t, 2H), 7.49-7.53 (m, 1H), 7.56-7.59 (m, 1H), 7.72 (t, 1H), 7.87 (t, 1H), 7.99-8.02 (m, 2H), 8.46 (s, 1H), 8.59 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 493.95.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C:4]=12)=O.C([O-])(=O)C.[NH4+].[N+:29]([CH3:32])([O-:31])=[O:30]>O>[N+:29](/[CH:32]=[CH:1]/[C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C:4]=12)([O-:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCc2c(C=O)c3ccccc3n2CC1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(/C=C/[N+](=O)[O-])c3ccccc3n2CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 11-formyl-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate (314 gm, 1.0 mmol) in nitromethane (1 mL) is treated with ammonium acetate (23 mg, 0.3 mmol) and heated to reflux. After 18 hrs, the resulting dark brown solution is cooled to rt, diluted with water (15 mL), and extracted twice with dichloromethane (20 mL). The combined organics are washed with brine (15 mL), dried over MgSO4, filtered, and concentrated to give a crude solid. This material is purified by LC (230-400 silica gel) eluting with 10:40:50 ethyl acetate/dichloromethane/heptane to afford 240 mg of tert-butyl 11-[(E)-2-nitroethenyl]-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate as a bright yellow solid, mp 227-230° C. IR (drift) 1692, 1621, 1493, 1472, 1419, 1323, 1310, 1302, 1291, 1277, 1259, 1248, 1198, 1164, 751 cm−1; MS (EI) m/z 357 (M+).