Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[F:8][C:9]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>O.C(Cl)(Cl)Cl>[CH3:26][N:27]([C:28]([N:15]1[CH2:16][CH2:17][CH:12]([O:11][C:10]2[C:18]([F:25])=[C:19]([F:24])[C:20]([F:23])=[C:21]([F:22])[C:9]=2[F:8])[CH2:13][CH2:14]1)=[O:29])[CH3:31]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CN(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
To a stirring solution of 10 g of potassium carbonate in 50 ml of water was added 4.42 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride in 50 ml of chloroform, followed by a solution of 3.23 g of dimethylcarbamoyl chloride in 20 ml of chloroform which was added, dropwise, over a period of 20 minutes. After stirring for 20 hours at room temperature, the layers were separated; the organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the filtrate afforded an oil. The oil was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane) to afford 3.50 g (69.0%) of 1-[(N,N-dimethylamino)carbonyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[N:20][OH:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](OC(=O)C)(=O)[CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(Cc2ccc(SC)cc2)=NO)cc1F
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(-c2noc(C)c2-c2ccc(SC)cc2)cc1F
Yield: 30 %

Procedure:
3-(3-Fluoro-4-methoxyphenyl)-5-methyl-4-[4-(methylthio)phenyl]isoxazole was prepared in 30% yield from 1-(3-fluoro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one oxime from Step 2 and acetic anhydride by the procedure described in Example 4, Step 1 and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13][N:12]=1>CN(C=O)C.[H-].[Na+]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:13][N:12]=1
Reactant: COc1ccc2c(Cl)nnc(CCCCc3ccccc3)c2c1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(CCCCc3ccccc3)c2c1
Yield: 25.9 %

Procedure:
Operating substantially as described in example 5 starting from 3,5-dichloro-4-methyl-pyridine (0.23 g, 1.4 mmoles) in dry DMF (10 ml), 55% NaH in oil (0.061 g, 1.4 mmoles) and 1-chloro-6-methoxy-4-(4-phenyl-butyl)phthalazine (0.23 g, 0.7 mmole), prepared as described in example 20, in DMF (5 ml), 0.082 g of the title compound were obtained in form of amorphous hygroscopic solid (yield: 21%).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]c(=O)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of 0.3 g of 7-nitro-3H-benzooxazol-2-one (1.67 mmol) in 5 ml of ethanol was degassed and then 0.03 g (10% by weight) of palladium on carbon (5%-50% wet) was added thereto. The reaction medium was stirred under a hydrogen atmosphere for 2 hours at ambient temperature. The reaction medium was filtered through celite and concentrated to dryness. 0.25 g of product was obtained in the form of a colorless oil. Yield=99%.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.Br[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:35]1([CH2:34][CH2:33][CH2:32][C:2]#[C:3][CH2:4][CH2:5][C:6]2[N:7]=[CH:8][NH:9][CH:10]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrC(Br)=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: BrCCCc1ccccc1
Product: C(#CCCc1c[nH]cn1)CCCc1ccccc1

Procedure:
4-(7-Phenylhept-3-ynyl)imidazole was prepared in the same manner as described in example 36 except that 4-(4,4-dibromobut-3-enyl)-1-(triphenylmethyl)imidazole and 1-bromo-3-phenylpropane were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.Cl[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36]>>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][N:20]1[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:6]2[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]3)/[S:22][C:21]1=[O:23]
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: CN(C)CCCl
Agent: Cl
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN(C)C)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-3-[2-(Dimethylamino)ethyl]-5-[(1-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 2-chloro-N,N-dimethylethylamine hydrochloride following General Procedure H.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].Br[CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1>CN(C)C=O>[NH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([CH2:26][CH2:25][N:5]2[CH2:6][CH:7]3[CH:3]([C:2]3([C:8]3[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=3)[CH3:1])[CH2:4]2)=[CH:28]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCc3c[nH]c4ccccc34)CC21
Temperature: 55 °C

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 50 mg, 0.165 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (35 mg, 0.413 mmol) and 3-(2-bromoethyl)indole (37 mg, 0.165 mmol). The reaction mixture was heated at 55° C. for 48 h, cooled to room temperature and concentrated in vacuo. Water (10 ml) was added and the product was extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g), eluting with hexane:ethyl acetate (100:0 and then 0:100). The title compound was obtained as a glass (22 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:18]([NH:26][C:27]([NH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred solution of 2-amino-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one (Example 6, 0.5 g, 2.22 mmol) in 20 mL of THF was cooled to 0° C. (ice/water bath). Benzoyl isothiocyanate was added dropwise over a period of 10 min. The mixture was warmed to room temperature and stirred for 20 hr. The solvent was evaporated and the yellow solid washed with 50 mL of 1:1 ethyl acetate/hexanes solution (yield 0.736 g, 85%). H1 NMR (DMSO d6) δ: 12.43 (s, 1H), 11.53 (s, 1H), 9.92 (s, 1H), 8.00-7.95 (m, 3H), 7.06-6.96 (m, 6H), MS (ES): MH+ 389.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:5]([C:24]#[N:25])=[CH:4][N:3]=1>C(O)(=O)C.[Ni]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:24][N:25]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]3[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=3[C:6]=2[N:7]=1
Reactant: N#Cc1cnc(N)nc1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [Ni]
Solvent: CC(=O)O
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 2.5 h

Procedure:
A solution of 50 mg (0.142 mmole) of the end product of Example 10 in 10 ml of acetic acid was treated with 1/4 spatula of Raney nickel, and hydrogenated for 2.5 hrs. The reaction was filtered through celite, evaporated, and partitioned between 30 ml of dichloromethane and 15 ml of dilute ammonium hydroxide. The organic layer was dried with sodium sulfate, evaporated and the residue was refluxed in ethanol for 1 hr, and then evaporated to dryness. The solid was dissolved in dichloromethane and developed on a thick layer silica gel plate in ethyl acetate/ethanol (20/1). The band of Rf 0.3 was removed and crystallized from ether to give white prisms, mp 243°-248° C., and a mixed mp of 244°-248° C. with authentic material obtained as in Example 2.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[CH2:24]([NH2:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([NH:32][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:15])[C:8]([CH3:11])=[CH:9][N:10]=1
Reactant: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)O
Reactant: NCCc1ccccc1
Product: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)NCCc1ccccc1

Procedure:
8-1 was prepared from [3-(2,2-difluoro-2-pyridin-2-ylethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and phenethylamine essentially according to the procedure of Example 1, Step K. Mass Spectrum: Found: (M+1) 428.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].[OH-:25].[Na+].Cl>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:25])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a test tube (outside diameter: 21 mm φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazine-3-one ((2-34)-(1)-39) (62.8 mg), dimethylsulfoxide (0.5 ml), and 3.8% by weight of aqueous sodium hydroxide solution (0.5 ml) were added under a nitrogen atmosphere at room temperature, and stirred at 70° C. for 4 hours. Then, to the reaction mixture was added 3.5% by weight of hydrochloric acid (4 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 37.5 mg of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH:44][CH2:45][CH2:46][N:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]1=[O:57])(=[O:43])=[O:42])([O-:34])=[O:33].[CH2:58]([N:60]1[C:66](=[O:67])[C:65]([CH3:69])([CH3:68])[C:64](=[O:70])[N:63]([CH3:71])[C:62]2[CH:72]=[C:73]([CH2:76][CH2:77][CH2:78]O)[CH:74]=[CH:75][C:61]1=2)[CH3:59]>O.C1(C)C=CC=CC=1>[CH2:58]([N:60]1[C:66](=[O:67])[C:65]([CH3:69])([CH3:68])[C:64](=[O:70])[N:63]([CH3:71])[C:62]2[CH:72]=[C:73]([CH2:76][CH2:77][CH2:78][N:44]([CH2:45][CH2:46][N:47]3[CH:56]=[CH:55][C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:48]3=[O:57])[S:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N+:32]([O-:34])=[O:33])(=[O:42])=[O:43])[CH:74]=[CH:75][C:61]1=2)[CH3:59]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCO)ccc21
Reactant: O=c1c2ccccc2ccn1CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCN(CCn3ccc4ccccc4c3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Reaction time: 8 h
Yield: 26.5 %

Procedure:
Tributyl phosphine (1.2 ml) and 1,1′-(azodicarbonyl)dipiperidine (1.17 g) were added to a toluene solution (100 ml) of 2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)-ethyl]-benzenesulfonamide (1.39 g), and 1-ethyl-7-(3-hydroxy-propyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.94 g). The mixture was stirred overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and saturated saline, dried with magnecium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→1:0). The purified product was condensed under reduced pressure to produce the title compound (0.54 g) as a white amorphous.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>>[CH3:14][Si:15]([C:18]#[C:19][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: COC(=O)CCc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Product: COC(=O)CCc1ccc(C#C[Si](C)(C)C)cc1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (250 mg, 0.86 mmol) and trimethylsilylacetylene (0.22 mL, 1.70 mmol) according to the general procedure IA. After filtration through Celite, the product was obtained as a brown oil and used without purification in the next step. Rf: 0.38 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.39-7.37 (m, 2H), 7.13-7.11 (m, 2H), 3.65 (s, 3H), 2.96-2.91 (t, 2H, J=7.6 Hz), 2.63-2.58 (t, 2H, J=7.8 Hz), 0.24 (s, 9H); 13CNMR (CDCl3) δ 173.1, 141.1, 132.1, 128.2, 121.1, 105.0, 93.8, 51.6, 35.6, 30.8, 0.0.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:13][CH:12]([NH:27]C(OC(C)(C)C)=O)[C:11]1=[O:35])(=[O:3])[CH3:2].Cl>C(OCC)(=O)C>[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[N:13][CH:12]([NH2:27])[C:11]1=[O:35])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sccc1CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(C2CCCCC2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1sccc1CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Yield: 82.7 %

Procedure:
To a solution of (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.379 g) in ethyl acetate (10 ml) was treated with hydrogen chloride under stirring. The mixture was extracted with water twice and 1N hydrogen chloride aqueous solution. The extracts were combined, alkalized with sodium bicarbonate and extracted with chloroform three times. The extracts were combined, dried over sodium sulfate and evaporated in vacuo to afford (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-amino-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.25 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[NH:14][C:15](=[O:19])[CH2:16][S:17][CH:18]=1.O>CC(C)=O>[OH:9][CH:16]1[C:15](=[O:19])[NH:14][C:13]([CH3:12])=[CH:18][S:17]1
Reactant: CC1=CSCC(=O)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: O
Product: CC1=CSC(O)C(=O)N1
Reaction time: 2 h
Yield: 46.9 %

Procedure:
m-Chloroperbenzoic acid (0.216 g) was added to 5-methyl-2H-1,4-thiazin-3(4H)-one (0.129 g) in dry acetone (4 ml) under ice-cooling and the mixture was stirred for 2 hours. Water was added to the mixture and the solution was stirred for 30 minutes. Then, the reaction mixture was further stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (Wakogel C-200) column, using ethyl acetate-n-hexane (=2:1) as an eluant to give 2-hydroxy-5-methyl-2H-1,4-thiazin-3(4H)-one (0.068 g, yield 46.9%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](P(O)(O)=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].N12CCCN=C1CCCCC2.[CH3:32][CH:33]1[CH2:36][CH:35]([CH:37]=O)[CH2:34]1>ClCCl>[CH3:1][O:2][C:3](=[O:20])/[C:4](/[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[CH:32]/[CH:33]1[CH2:36][CH:35]([CH3:37])[CH2:34]1
Reactant: CC1CC(C=O)C1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C(=C/C1CC(C)C1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
In a round bottom flask under argon was placed N-(benzyloxycarbonyl)-α-phosphonoglycine methyl ester (3.04 g, 9.16 mmol) in dichloromethane (10 mL) and cooled to 0° C. This mixture was treated dropwise with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.20 mL, 7.94 mmol) and stirred at 0° C. for 20 min. A solution of 3-methyl-cyclobutanecarbaldehyde (600 mg, 6.11 mmol) in dichloromethane (5 mL) was then added. After the addition was complete the reaction was warmed to 25° C. and stirred overnight. The mixture was then concentrated in vacuo and dissolved in ethyl acetate (100 mL). The ethyl acetate layer was washed with a saturated aqueous ammonium chloride solution (2×50 mL), a saturated aqueous solution of sodium chloride (50 mL), dried over sodium sulfate and concentrated in vacuo with silica gel (3 g). Purification by Biotage flash chromatography (40M column, 20% ethyl acetate/hexanes) afforded (Z)-2-benzyloxycarbonylamino-3-(3-methyl-cyclobutyl)-acrylic acid methyl ester (693 mg, 38%) as a yellow viscous oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:20]([N:22]([CH2:45][CH3:46])[CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[C:29]([Br:35])[CH:30]=[C:31](I)[CH:32]=2)[C:27]([OH:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:26]1=[O:44])[CH3:21].[CH3:47][N:48](C=O)C>CCOC(C)=O.C1(C)C=CC=CC=1.[C-]#N.[C-]#N.[Zn+2]>[CH2:20]([N:22]([CH2:45][CH3:46])[CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[C:29]([Br:35])[CH:30]=[C:31]([C:47]#[N:48])[CH:32]=2)[C:27]([OH:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:26]1=[O:44])[CH3:21]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(I)cc21
Agent: [C-]#N
Agent: [Zn+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To Pd2(dba)3CHCl3 (60.1 mg, 5 mol %) and PPh3 (60.9 mg, 20 mol %) under a nitrogen atmosphere was added anhydrous DMF (0.5 mL). The resulting precipitate was stirred at room temperature for 30 minutes during which time the colour changed from red to yellow/orange. To this was added 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-bromo-6-iodooxindole (626.4 mg, 1.16 mmol) dissolved in anhydrous DMF (1.0 mL). To the resulting red solution was then added Zn(CN)2. The resulting precipitate was then heated to 60° C. (bath temperature) and stirring was continued at that temperature for 4 hours. The mixture was allowed to cool to room temperature and diluted with EtOAc:toluene (1:1, 10 mL). The mixture was washed with H2O (6 mL). The aqueous phase was then extracted with EtOAc:toluene (1:1, 5 mL×5). The organic phases were combined and dried (anhydrous MgSO4). After filtration the solvent was removed in vacuo. The orange solid obtained was then purified by flash chromatography (silica gel, eluting 1% to 2% to 3%MeOH in CHCl3) to give the title compound as a light brown/orange solid (462.6 mg, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CCO.[OH-].[Na+]>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:19]2[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24]2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C(=O)O)cc2)CC(C)(C)C1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a round-bottomed flask was added methyl 4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoate (25) (8.06 g, 21 mmoL), EtOH (100 mL), and THF (100 mL). To the solution was added 1 N aqueous NaOH (200 mL). The reaction mixture was stirred at 65° C. under a nitrogen atmosphere for 3 h. The reaction mixture was partially concentrated in vacuo to remove the EtOH and THF. The aqueous mixture was cooled in an ice-water bath and 1 N aqueous HCl was slowly added to pH ˜1. The acidic aqueous suspension was extracted with CH2Cl2 (1 x) followed by EtOAc (3 x). Those EtOAc extracts that contained the majority of product, as indicated by TLC, were independently washed with brine, combined, dried over MgSO4, filtered, and the filtrate was concentrated to give 6.0 g of the crude product as a pale tan solid. The CH2Cl2 extract noted above was concentrated to give 1.9 g of the crude product as an off-white solid. The two crops of crude product were combined and purified by flash chromatography on silica gel with CH2Cl2:MeOH (95:5) to give 6.07 g (79%) of compound 26 as a white solid. A portion of the product was dried under vacuum at 90° C. to give the following 1H NMR data. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.88 (s, 6H), 1.24 (s, 2H), 1.85 (s, 2H), 1.92 (s, 2H), 6.66 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 9.30 (s, 2H), 12.78 (br s, 1H). The compound was silylated prior to EI analysis. HRMS (EI) Calcd for C30H44O3Si2: 508.2829 (M+). Found: 508.2833.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Cl:28])C(=O)C1>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:28])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: ClCc1ccnc(Cl)c1

Procedure:
10 g of 2-chloro-4-methylpyridine are dissolved in 30 ml of CH3CN and a mixture of AIBN (3 g) and NCS (30 g) is added. The resulting mixture is refluxed for 4 hours. After removing the solvent, the crude product is further purified by distillation (boiling point: 70° C., 20 mtorr).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6](C(O)=O)=[C:5]2[OH:16]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:16]
Reactant: Cc1cc(Br)cc2c(O)c(C(=O)O)cnc12
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc(Br)cc2c(O)ccnc12
Temperature: 260 °C
Yield: 94.4 %

Procedure:
A mixture of 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylic acid (1.80 g, 6.36 mmol) and Dowtherm A (10 mL) was heated at 260° C. for 1.0 h. The reaction was cooled, triturated with hexanes, filtered and dried in a Buchner funnel to give the title compound (1.43 g, 95%) as a tan solid. MS(ES)+m/e 238 [M+H].