Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3]C(N(C)C)=O.[F:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][N:15]2[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[N:17]=[C:16]2[NH2:26])=[CH:12][CH:11]=1.CI>O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[N:17]([CH3:3])[C:16]2=[NH:26])=[CH:27][CH:28]=1
Reactant: Nc1nc(=O)c2cccnc2n1Cc1ccc(F)cc1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(=O)c2cccnc2n(Cc2ccc(F)cc2)c1=N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.4 g. of sodium hydride in 60 ml. of dimethylacetamide is added 2.5 g. of 1-(4'-fluorobenzyl)-2-amino-pyrido[2,3-d]pyrimidin-4(1H)-one while maintaining the system under nitrogen. After stirring for one hour at room temperature, the mixture is treated by addition of 1.0 ml. of methyliodide. The resulting mixture is stirred at 20°C. for 15 hours. A small amount of water (ca 1.0 ml.) is then added and the mixture evaporated in vacuo. The residue is treated with ice/water and the resulting precipitate is recovered by filtering, washed with water and dried. The dried precipitate is then dissolved in methylene chloride, treated with charcoal and filtered through neutral alumina. The filtrate is concentrated in vacuo and ether added to obtain on crystallization 1-(4'-fluorobenzyl)-2,3-dihydro-2-imino-3-methyl-pyrido[2,3-d]pyrimidin-4(1H)-one
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.S(Cl)([Cl:13])=O.CN(C=O)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: O=S(Cl)Cl
Reactant: Oc1ccnc2ccsc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccnc2ccsc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Thieno[3,2,b]pyridin-7-ol (200 mg; 1.32 mmol) was added to thionyl chloride (1.57 g; 13.2 mmol), followed by a drop of DMF. The solution was stirred at 80° C. for 4 hours. The cooled solution was diluted with ethyl acetate and neutralised to pH 7 with a saturated solution of sodium hydrogen carbonate (25 ml). The organic layer was washed with brine, dried and concentrated to yield the title compound (112 mg; 50%); Mass Spectrum: M+H+ 170.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:19]([Cl:20])=[C:18]([OH:21])[CH:17]=[CH:16][C:5]=1[C:6](=[N:14][OH:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.N#N.Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+].Cl>CN(C=O)C.O>[Cl:20][C:19]1[C:4]2[O:15][N:14]=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[C:5]=2[CH:16]=[CH:17][C:18]=1[O:21][CH2:25][C:26]([OH:28])=[O:27]
Reactant: ON=C(c1ccc(F)cc1)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: N#N
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc2c(-c3ccc(F)cc3)noc2c1Cl
Temperature: 96 °C
Reaction time: 1 h

Procedure:
To a mixture of 4.0 g NaH in 50 ml DMF, a solution of 20 g of 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone oxime in 100 ml of DMF is added dropwise in an atmosphere of N2. The reaction mixture is heated to an internal temperature of 96° C. for 2 hours. The reaction mixture is cooled to 40° C. and 12.3 g of ethyl bromoacetate is added dropwise and the mixture is stirred for one hour. Twenty milliliters of 50% NaOH and 100 ml of water is added and the reaction is heated at 80°-90° C. for one hour. Concentrated HCl is added until the reaction mixture is acidic and the mixture is stirred for one half hour and water added. A solid product is collected by filtration and recrystallized to give a pure product of {[7-chloro-3-(4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 233°-237° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:38])[CH2:11][CH2:12][N:13]([C:20](=[O:37])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:14][C:15](OCC)=[O:16])[CH3:8].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([CH:11]1[C:15](=[O:16])[CH2:14][N:13]([C:20](=[O:37])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:12]1)=[O:38])[CH3:8]
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCNC(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CN(C(=O)CCCCCNC(=O)OCc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of potassium t-butoxide (7.12 g, 64 mmol) in toluene (150 mL) at 0° C. under nitrogen, was added diester 59 (20 g, 44 mmol) in toluene (25 mL) over a 10 min period. The solution was stirred for 30 min at 0° C. and 5 mL of glacial acetic acid was added, immediately followed by 25 g of NaH2PO4.H2O in 250 mL of ice-cold water. The resultant mixture was extracted with chloroform (3×200 mL), and the combined organic extracts were washed twice with phosphate buffer (2×25 mL, pH=7.0), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in toluene (300 mL), cooled to 0° C., and extracted with cold pH 9.5 carbonate buffer (3×150 mL). The aqueous extracts were converted to pH 3 with phosphoric acid, and extracted with chloroform (5×125 mL) which were combined, dried, and evaporated to a afford keto ester 60 (12 g, 45%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[BH4-].[Na+]>CCO.CCOC(C)=O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a solution of 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (P-3; 2.59 g, 7.79 mmol) in EtOH (120 mL), sodium borohydride (725.8 mg, 19.18 mmol) was added as a solid in portions at room temperature. After the addition was complete, the mixture was stirred at room temperature for 90 minutes (min). The mixture was then diluted with EtOAc and washed with H2O. The aqueous fraction was extracted with EtOAc. The organic fractions were combined, dried over anhydrous MgSO4, and evaporated at room temperature under vacuum. The crude material was absorbed to silica gel with EtOAc and eluted with 50% EtOAc in hexane. The title product (2.43 g, 93%) was isolated as a white solid: mp 112-114° C.; 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 8.29-8.12 (m, 2H), 7.91-7.69 (m, 2H), 7.43 (ddd, J=9.0, 5.7, 4.5 Hz, 4H), 4.78 (d, J=6.0 Hz, 2H), 2.07 (t, J=6.0 Hz, 1H); ESIMS m/z 336 (M+H).
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1.[CH3:13][N:14]([CH2:19][C:20]1[O:21][C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]=1[CH3:25])[C:15](=[O:18])[CH:16]=[CH2:17].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH3:13][N:14]([CH2:19][C:20]1[O:21][C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]=1[CH3:25])[C:15](=[O:18])/[CH:16]=[CH:17]/[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Reactant: Brc1cnc2c(c1)NCCCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)NCCCN3)oc2ccccc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
A solution of 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin (0.15 g, 0.66 mmol), N-methyl-N-((3-methyl benzofuran-2-yl)methyl)acrylamide (0.30 g, 1.32 mmol), (i-Pr)2EtN (0.34 mL, 2.0 mmol) tn DMF (7 mL) was de-oxygenated with Ar for 30 min. Pd(OAc)2 (15 mg, 0.066 mmol) and P(o-tol)3 (40 mg, 0.13 mmol) was added and the solution was de-oxygenated for an additional 15 min. The reaction was heated to 100° C. for 18 hrs at which time the reaction was cooled to room temperature and then filtered through a short-column of silica washing with EtOAc (20 mL). The filtrate was washed with brine (2×30 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (111 mg, 45%) as a yellow powder; 1H NMR (400 MHz, DMSO-d6) δ7.75 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6, 1H), 7.43 and 7.39 (2×s, 1H), 7.35-7.22 (m, 3H), 7.08 and 6.82 (2×d, J=15, 1H), 6.22 (s, 1H), 5.25 (s, 1H), 4.90 and 478 (2×s, 2H), 3.14-2.93 (m, 7H), 2.26 (s, 3H), 1.68 (m, 2H); ESI MS m/z 377 [C22H24N4O2+H]+
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][NH:13][C:12]1=[S:16].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(O)C.CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[C:12]1=[S:16]
Reactant: C=CC(=O)OCC
Reactant: S=c1[nH]ccn1C1CCc2ccccc2C1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CCn1ccn(C2CCc3ccccc3C2)c1=S
Temperature: 80 °C
Yield: 66.1 %

Procedure:
A mixture of 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (1.3 g, 5.6 mmol), prepared as in Example 9, and ethyl acrylate (3.1 mL, 28.2 mmol) in 14 mL of ethanol and 1.28 mL of N-benzyltrimethylammonium hydroxide (2.8 mmol) in methanol was heated at 80° C. under nitrogen for 2 hours. The mixture was allowed to cool and concentrated by rotoevaporation. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (3:1) to give ethyl 3-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl]propionate (1.2 g, 3.7 mmol), m.p. 71°-73° C.
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29]>CN(C)C=O.CCOCC>[C:28]([CH2:27][N:10]1[CH2:11][CH2:12][C@:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C@@H:8]2[CH2:9]1)#[N:29]
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#CCN1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Yield: 99.7 %

Procedure:
To a solution of 3.02 g of cis-1,2,3,4,4a,9b-hexahydro-4a-phenyl-benzofuro[3,2-c]pyridine in 48 ml of dry dimethylformamide was added 3.6 g of anhydrous potassium carbonate and 0.982 g of chloroacetonitrile. The resulting suspension was heated at 80° under nitrogen for 19 hours. The cooled reaction mixture was diluted with 500 ml of ether and washed with water (4×250 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give 3.48 g (99.9%) of a gum, which crystallized on standing. A 0.35 g portion of this material was recrystallized from ethanol to afford 0.22 g of crystals, m.p. s 93, 94°-96°.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.Br[CH2:38][CH2:39][OH:40]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][N:25]5[CH2:38][CH2:39][OH:40])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: OCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](O)CN1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](O)CN1CCO

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxy-1-(2-hydroxyethyl)pyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (Example 182) and 2-bromoethanol following General Procedure S.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[CH3:55][O:56][C:57](=[O:72])[C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][N:67]=[C:66]([CH2:70][NH2:71])[CH:65]=2)=[CH:60][CH:59]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:71][CH2:70][C:66]2[CH:65]=[C:64]([C:61]3[CH:62]=[CH:63][C:58]([C:57]([O:56][CH3:55])=[O:72])=[CH:59][CH:60]=3)[CH:69]=[CH:68][N:67]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: COC(=O)c1ccc(-c2ccnc(CN)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccnc(CNC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (275 mg, 1.2 mmol) in CH2Cl2 (2 ml) was added diisopropylethylamine (0.23 ml, 1.32 mmol). The resulting solution was stirred for 5 minutes then TBTU (337 mg, 1.26 mmol) was added and stirred for 20 minutes. To the reaction mixture was added a solution of 4-(2-aminomethyl-pyridin-4-yl)-benzoic acid methyl ester trifluoroacetic acid salt (356 mg, 1 mmol, reference example 103a) and diisopropylethylamine (0.192 ml, 1.1 mmol) in CH2Cl2 (2 ml). The reaction mixture was stirred 45 minutes then concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 40% ethyl acetate/10% methanol/hexanes) to give 455 mg of product as a white foam. MS (ion spray) m/z 454 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:17]([CH3:29])[CH2:16]2)=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].O.[OH-].[Li+]>O.O1CCOCC1>[CH3:28][C:25]([O:24][C:22]([N:18]1[C@@H:17]([CH3:29])[CH2:16][N:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:2]([CH3:1])([CH3:7])[C:3]([OH:5])=[O:4])=[CH:9][CH:10]=2)[CH2:20][C@H:19]1[CH3:21])=[O:23])([CH3:26])[CH3:27]
Reactant: COC(=O)C(C)(C)c1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2ccc(C(C)(C)C(=O)O)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.7 %

Procedure:
A mixture of D47 (395 mg, 0.978 mmol) and lithium hydroxide monohydrate (82 mg, 1.95 mmol) in water (5 ml) and 1,4-dioxane (10 ml) was stirred at room temperature for 3 days. The solvents were removed in vacuo and the residue dissolved in water. The solution was washed with ether, acidified to pH4 with 1M HCl then extracted with DCM (×2). The combined organics were dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow foam (316 mg). δH (CDCl3, 250 MHz) 7.35 (4H, m), 4.11 (2H, br), 3.71 (2H, br), 2.67 (2H, br), 2.17 (2H, br), 1.61 (6H, s), 1.46 (9H, s), 1.33 (6H, br d). MS (ES): MH+ 391, (M−H+) 389.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:6])[CH3:5].[OH-].[K+].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[C:12]([Cl:18])[CH:11]=1>O1CCCC1.C(OCC)C.C1OCCOCCOCCOCCOCCOC1>[Cl:18][C:12]1[CH:11]=[C:10]([F:9])[CH:17]=[CH:16][C:13]=1[CH2:14][N:3]([O:2][CH3:1])[C:4](=[O:6])[CH3:5]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CONC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CON(Cc1ccc(F)cc1Cl)C(C)=O
Temperature: 25 °C
Yield: 33.5 %

Procedure:
To a stirred mixture of 1.95 g (0.0219 mole) of N-methoxyacetamide, 1.23 g 0.022 mole) of powdered potassium hydroxide, and a small amount (~0.05 g) of 18-crown-6 in 10 ml of tetrahydrofuran was added a solution of 5.05 g (0.0226 mole) of 4-fluoro-2-chlorobenzyl bromide in 15 ml of tetrahydrofuran. This mixture was heated at reflux for approximately 17 hours and then was allowed to cool to room temperature. The mixture was diluted with 125 ml of diethyl ether and was washed with an aqueous, saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a yellow oil. This oil was purified by column chromatography on silica gel, eluting with ethyl acetate:n-heptane (25:75) followed by ethyl acetate:n-heptane (50:50) , to yield 1.7 g of N-(2-chloro-4-fluoro-benzyl)-N-methoxyacetamide as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:30])[C@:7]1(O)[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:27])([C@@H:22]([Br:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].BrN1C(=O)CCC1=O.S(=O)=O.Cl>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6](=[O:30])[C:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:27])([C@@H:22]([Br:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](Br)C[C@@]21C
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: O=S=O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](Br)C[C@]12C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 21-acetyloxy-11β-bromo-9-fluoro-17-hydroxypregn-4-ene-3,20-dione (4.0 g) in pyridine (10 ml) is cooled to 10° C. A solution of N-bromosuccinimide (2.0 g) in pyridine (7.0 ml) is added at 10° C and the mixture is warmed to room temperature and stirred for 10 minutes. It is recooled to 10° C and a solution of sulfur dioxide (2.2 g) in pyridine (10 ml) is added. The mixture is warmed to room temperature and then added slowly, with stirring into 1N hydrochloric acid (300 ml). The title compound is separated and purified.
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].C1C=C2C(OC(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)C2=CC=1)=O.C[O-].[Na+].C(=O)([O-])[O-].[K+].[K+].[F:42][C:43]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:44]=1[NH2:45].[OH-].[Na+].CCOCC>CO.CN(P(N(C)C)(N(C)C)=O)C>[F:42][C:43]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:44]=1[NH:45][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: Cc1ccc(N)c(F)c1
Reactant: CC(C)C(Br)C(=O)O
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(NC(C(=O)O)C(C)C)c(F)c1

Procedure:
A solution of α-bromoisovaleric acid (8.17 mmole) in methanol is titrated to the phenophthalein end point using sodium methoxide. The solvent is removed by rotoevaporation and then there is added potassium carbonate (1.69 g), 2-fluoro-4-methylaniline (16.38 mmole) and 3 ml HMPT. The reaction is heated at 60° for about 5 hours and then worked up with 5% sodium hydroxide/ether and washed with water (3×). The basic layer is acidified and extracted with ether, washed with water and brine, dried over sodium sulfate and rotoevaporated to yield α-(2-fluoro-4-methylphenylamino)isovaleric acid. (2-Fluoro-4-methylaniline is prepared from 3-fluoro-4-nitrotoluene in a Parr bottle using platinum oxide and hydrogen in ethanol.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][C:14]3[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11](=[O:24])[CH:10]2[CH2:25][CH2:26][CH3:27])=[CH:5][CH:4]=1.C(=O)(O)[O-].[K+].[I-].[K+].[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][Cl:39].Cl>CC(CC)=O.C1(C)C=CC=CC=1>[ClH:39].[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][N:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:14]=2[CH2:15][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@H:10]([CH2:25][CH2:26][CH3:27])[C:11]1=[O:24]
Reactant: CCCC1C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccc(OC)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: CCC[C@@H]1C(=O)N(CCN(C)C)c2cccc(C(F)(F)F)c2C[C@@H]1c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
To 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-propyl-6-(trifluoromethyl)-2H-1-benzazepin-2-one (4.23 g; 11.21 mmole), potassium bicarbonate (4.49 g; 44.8 mmole; 4 eq.), and potassium iodide (catalytic amount) suspended in methylethyl ketone (70 ml) was added a 2.15M solution of 2-dimethylaminoethyl chloride (12.6 ml; 27.0 mmole; 2.4 eq.) in toluene with stirring. The mixture was refluxed for 10.5 hours, then concentrated. The residue as dissolved into ethyl acetate and washed with water. The organic layer was dried (magnesium sulfate) and concentrated. The residue was flash chromatographed (silica gel column/0.5% methanol:dichloromethane followed by 2.0% methanol:dichloromethane) and appropriate fractions were combined and concentrated. The residue was dissolved in ether and hydrogen chloride saturated ether was added. The mixture was concentrated, and coevaporated with ether several times. The solid was partitioned between ether and 1N sodium bicarbonate. The ether layer was dried (magnesium sulfate) and concentrated. After standing overnight, the solid residue was much less soluble in ether. The solid was triturated in ether and the mixture was centrifuged and a solid was obtained. Conversion to the hydrochloride salt using hydrogen chloride saturated ether yielded the title compound, melting point 180.5°-182.5° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Br-].[F:10][C:11]([F:19])([F:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I>[F:10][C:11]([F:19])([F:18])[C:12]1[CH:17]=[CH:16][C:15]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: O=C(O)[C@@H]1CCCN1c1ccc(C(F)(F)F)cc1
Temperature: 90 °C

Procedure:
A reaction vessel containing L-proline, 4-trifluoromethylbenzenebromide, potassium carbonate and copper iodide is evacuated and purged with argon several times. Dimethylformamide is added and the solution is heated at 90° C. for 4 days in a sealed vessel. After this time, the mixture is cooled to room temperature and diluted with ethyl acetate and water. The two layers are separated and the aqueous is acidified to pH3 using concentrated hydrochloric acid and extracted with ethyl acetate. The combined organics are washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford title compound as intermediate which is used crude in subsequent reactions. ESI m/z 260 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=1)[CH3:9]>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:8][CH3:9])=[CH:11][CH:12]=1
Reactant: BrCCCCCBr
Reactant: CCc1ccc(CCO)cc1
Product: CCc1ccc(CCOCCCCCBr)cc1

Procedure:
(2.19 g) T.l.c. [K] Rf 0.48, from 1,5-dibromopentane (7.8 g) and 4- ethylbenzeneethanol (1.7 g).