Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[Br:12][C:5]1[CH:6]=[CH:7][C:8]([N:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)c1cccc(N)c1Cl
Solvent: CN(C)C=O
Product: CN(C)c1ccc(Br)c(N)c1Cl
Temperature: 0 °C
Reaction time: 48 h
Yield: 93.5 %

Procedure:
12.8 g of 2-chloro-3-dimethylaminoaniline is dissolved in 180 ml of DMF and stirred at 0° C. A solution of 13.4 g of N-bromosuccinimide in 80 ml of DMF is slowly added dropwise, so that the temperature does not rise above 2° C. The mixture is stirred for 5 hours at 0° C. and then at RT. After 48 hours, 700 ml of ice-water is added. The white precipitate is filtered off and the aqueous phase is extracted three times with 200 ml of diethyl ether. The organic phases are dried, filtered, and evaporated down. 17.5 g of 2-bromo-6-chloro-5-dimethylaminoaniline is obtained as a brown oil and used further without any additional purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16](C3C=CC=CC=3Cl)[C:3]=12.[Cl:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)C(CC#N)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:35]3[CH:34]=[CH:28][CH:27]=[C:26]([Cl:25])[CH:36]=3)[C:3]=12
Reactant: N#CCC(=O)c1cccc(Cl)c1
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Product: Cn1nc(-c2cccc(Cl)c2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 13 was synthesised following similar procedures outlined in Example 1 (Compound 37), using 3-chlorobenzoylacetonitrile instead of 2-chlorobenzoyl acetonitrile in Step 1.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[F:32].C(O)C.O.Cl>>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[F:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Yield: 79 %

Procedure:
A mixture of 0.1 g (0.32 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.059 g (0.57 mmole) of 4-amino-3-fluoro-benzoic acid and 0.7 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[C:10]([NH2:27])=[N:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:14]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.[Cu]I.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:24]([S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:9]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[C:10]([NH2:27])=[N:11][CH:12]=2)=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH3:26])[CH3:25]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#C[Si](C)(C)C)n2)cc1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
Triethylamine (47.58 g, 65.54 mL, 470.2 mmol) was added to a stirred suspension of 3-bromo-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (33.5 g, 94.04 mmol) in anhydrous DMF (234.5 mL). Copper(I) iodide (2.148 g, 11.28 mmol) was then added followed by Pd(PPh3)4 (5.433 g, 4.702 mmol). The stirred mixture was cooled to 0° C. in an ice-bath and (trimethylsilyl)acetylene (12.01 g, 17.28 mL, 122.3 mmol) was added dropwise over 10 minutes. The ice bath was then removed and the mixture allowed to warm to ambient temperature over 2 hours. The mixture was poured into EtOAc/water (500 mL/300 mL) and the mixture was filtered through a pad of celite. The organic phase was separated and the aqueous layer extracted with EtOAc. The combined organics were washed with water (×1) and brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 750 g column, eluting with 0 to 15% DCM/EtOAc, dry-loaded) to give the sub-title product as a dark yellow solid (28.0 g, 78% Yield). 1H NMR (400.0 MHz, DMSO) δ 0.15 (s, 9H, 1.03 (d, 6H), 3.29 (sept, 1H), 6.80 (br s, 2H), 7.74 (d, 2H), 8.05 (d, 2H) and 8.60 (s, 1H) ppm; MS (ES+) 375.1.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]2([NH2:12])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=1.CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:13][C:14]1[N:15]=[C:16]([NH2:21])[N:17]=[C:18]([NH:12][C:9]2([CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][CH2:10]2)[CH:19]=1
Reactant: NC1(Cc2ccccc2)CC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NC2(Cc3ccccc3)CC2)n1
Temperature: 140 °C
Yield: 41.2 %

Procedure:
A mixture of 1-(phenylmethyl)cyclopropanamine_hydrochloride (530 mg, 2.88 mmol), 4,6-dichloro-2-pyrimidinamine (295 mg, 1.80 mmol), Et3N (911 mg, 9 mmol) and K2CO3 (249 mg, 1.80 mmol) in ethanol (6 mL) was stirred and heated at 140° C. for 4 hours in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated to dryness. The resulting solids were partitioned between EtOAc and water. The organic layer was separated, dried (Na2SO4), concentrated to dryness and purified by reverse phase chromatography using CH3CN in water from 32% to 42% (0.05% trifluoroacetic acid in water) in 8 min to afford the title compound (204 mg) as a white solid. LC-MS (ES) m/z=275 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=2)[CH2:4][O:3]1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=2)[CH2:4][O:3]1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(NC2COC(C)(C)OC2)n1
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(N)c(NC2COC(C)(C)OC2)n1

Procedure:
N-(2,2-Dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)-3-nitro-2-pyridinamine (35.00 g, 123.6 mmol) was divided into 2 aliquots, each of which was taken up in 1,4-dioxane (500 ml) and hydrogenated over 10% Pd on carbon (paste, 1:1 w:w with water, 4.00 g) under 1 atmosphere hydrogen pressure, at room temperature for 18 h. The mixtures were filtered with suction though Celite, using argon blanket and taking care to minimise contact of the product with air. The solids were washed with 1,4-dioxane and the combined filtrate plus washings were evaporated under reduced pressure to give the title compound as a deep purple oil. This was used immediately in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:39][CH2:40][C:41]1[C:46]([CH2:47][CH3:48])=[N:45][C:44]2[N:49]([CH2:52][CH3:53])[N:50]=[CH:51][C:43]=2[C:42]=1[NH:54][CH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>ClCCl>[CH2:52]([N:49]1[C:44]2=[N:45][C:46]([CH2:47][CH3:48])=[C:41]([CH2:40][NH:39][C:11]([C:9]3[N:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][CH:8]=3)=[O:13])[C:42]([NH:54][CH:55]3[CH2:56][CH2:57][O:58][CH2:59][CH2:60]3)=[C:43]2[CH:51]=[N:50]1)[CH3:53]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)n1
Temperature: 25 °C
Yield: 87 %

Procedure:
6-[(Methyloxy)carbonyl]-2-pyridinecarboxylic acid (272 mg, 1.500 mmol) was dissolved in dichloromethane (50 mL) and stirred under argon at room temperature. Then HBTU (569 mg, 1.500 mmol) was added followed by 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (510 mg, 1.5 mmol) and then the TEA (0.418 mL, 3.00 mmol). The mixture was stirred under argon overnight. The solvent was evaporated, and the residue partitioned between EtOAc (75 mL) and water (25 ml). The organic phase was washed with water (3×25 mL), brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude residue. It was purified by CombiFlash on a 12 gram silica column eluted with 60-100% EtOAc in hexane. Product fractions were combined and concentrated to give methyl 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylate (609 mg, 1.305 mmol, 87% yield) as a white solid. LC-MS m/z 467 (M+H)+, 0.74 min (ret time).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15](=[O:16])/[C:14](=[CH:17]/[C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[C:35]([F:38])([F:37])[F:36])[N:22]=[CH:21]4)/[S:13][C:12]2=[O:39])[CH:5]=1.C(CN)O>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:23]2[C:24]3[C:20](=[CH:19][C:18](/[CH:17]=[C:14]4/[C:15](=[O:16])[N:11]([CH2:10][C:6]5[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=5)[C:3]([OH:40])=[O:2])[C:12](=[O:39])[S:13]/4)=[CH:26][CH:25]=3)[CH:21]=[N:22]2)=[C:29]([C:35]([F:37])([F:36])[F:38])[CH:30]=1
Reactant: COC(=O)c1cccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)c1
Solvent: NCCO
Product: O=C(O)c1cccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)c1

Procedure:
3-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid was prepared from 3-{[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid methyl ester following General Procedure 0 and converted to the corresponding ethanolamine salt following General Procedure T.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]([O:29][N:30]=C(C)C)=[C:24]([C:26](=O)[CH3:27])[CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(O)C>[CH3:42][C@@H:37]1[CH2:36][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:25][C:24]3[C:26]([CH3:27])=[N:30][O:29][C:23]=3[C:22]=2[F:34])[CH2:40][C@H:39]([CH3:41])[O:38]1
Reactant: CC(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1ON=C(C)C
Agent: Cl
Solvent: CCO
Product: Cc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Yield: 39 %

Procedure:
To a stirred solution of 1-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-3-fluoro-2-(propan-2-ylideneaminooxy)phenyl)ethanone (Intermediate 32, 77 mg, 0.13 mmol, crude reaction product from above reaction) dissolved in ethanol (5 ml) was treated with 5 ml of 5% aqueous HCl at 75° C. for 2 hours. Reaction quenched with 10% aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer washed with water, dried, and concentrated. The residue purified over a silica gel flash coulmn (elution with 50-70% EtOAc in hexanes) to give the title compound (15 mg, 39%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11](=[CH:14]N(C)C)[CH:10]2[CH2:18][CH:19]=[CH:20][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[O:22]1CCOCC1>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][OH:22])[CH:10]2[CH2:18][CH:19]=[CH:20][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C1C(=O)N(C(=O)OC(C)(C)C)C2C=CCC12
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C(=CO)C2CC=CC21
Yield: 93 %

Procedure:
A solution of tert-butyl-3-(dimethylaminomethylene)-2-oxo-4,6a-dihydro-3aH-cyclopenta[b]pyrrole-1-carboxylate III-1 (120 mg, 0.43 mmol) in dioxane (9 mL) was stirred with hydrochloric acid (2 M, 0.86 mL, 1.72 mmol) for 15 h at room temperature. The solution was diluted with ethyl acetate, washed with water and brine, dried, concentrated giving the desired compound as a colorless oil (101 mg, 93%); 1H NMR (400 MHz, CDCl3) 9.92 (1H, d), 7.05 (1H, d), 6.91 (1H, m), 5.71 (1H, m), 5.07 (1H, d), 3.46 (1H, dt), 2.87 (1H, dd), 2.31 (1H, m), 1.55 (9H, s). LCMS (Method A): 0.79 min; ES−250 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[NH:11][C:10]1=[O:23].[H-].[Na+].I[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[N:11]([CH2:27][CH3:28])[C:10]1=[O:23]
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Temperature: 90 °C
Yield: 93 %

Procedure:
A solution, cooled in ice, of 100 mg (0.27 ml) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 6 ml of dimethylformamide was treated with 11 mg (0.27 mmol) of sodium hydride (60% w/w). After 30 minutes the mixture was treated with 0.03 ml (0.3 mmol) of iodoethane and then heated to 90° C. for 2 hours. The mixture was evaporated and the residue was treated with 30 ml of dichloromethane and 30 ml of water. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to give 100 mg (92%) of 3-(2,6-dichlorophenyl)-1-ethyl-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20](=[O:23])[NH:21][CH3:22])[CH:12]=1)=[O:10])C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[CH3:22][NH:21][C:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]([OH:10])=[O:8])=[CH:12]1)=[O:23]
Reactant: CNC(=O)n1cc(C(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)n1cc(C(=O)O)c2ccccc21
Reaction time: 1 h

Procedure:
To 1-Methylcarbamoyl-1H-indole-3-carboxylic acid benzyl ester (115 mg, 0.373 mmol) dissolved in a mixture of MeOH/CH2Cl2 1-1 (4 mL), Pd/C 10% (20 mg) was added and the solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere for 1 h. The mixture was placed under a nitrogen atmosphere and the catalyst was removed through a pad of Celite and washed with MeOH. Solvents were concentrated under vacuum to give the desired compound. MS (LC/MS): 219.1 [M+H]+; tR (HPLC conditions a): 2.54 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C>ClCCl>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCN(CCCCO)c1ccc(C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(CCCCOC(C)=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 249.4 g (1 mole) of 4-(N-4-hydroxybutyl-N-butylamino)benzaldehyde in dichloromethane are added 153.1 g (1.5 moles) of acetic anhydride, 151.8 g (1.5 moles) of triethylamine, and 8.5 g (7 mole %) of 4-N,N-dimethylaminopyridine. The reaction mixture is stirred at room temperature for 16 hours. The product solution is washed with cold 2N HCl and then with filtered through cotton, and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH:15]2[O:16][CH2:17][CH:18]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[CH:14]2[O:13][CH2:12]1>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH:15]3[O:16][CH2:17][CH:18]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH:14]3[O:13][CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1C1COC2C(Nc3nc(Cl)ncc3Cl)COC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1.45 g, 7.9 mmol) in MeOH (40 mL) were added triethanamine (970 mg, 9.6 mmol) and 2-(6-aminohexahydrofuro[3,2-b]furan-3-yl)isoindoline-1,3-dione (crude product from above step). The mixture was stirred at room temperature overnight, Then concentrated in vacuo, the residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/3) to give the desired compound as a white solid (450 mg, 13.5% three steps).
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[C:11](=[S:21])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O-].[Na+].CI>CO>[CH2:1]([C:8]1[N:12]([CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[C:11]([S:21][CH3:22])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(Cn1c(Cc2ccccc2)n[nH]c1=S)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CCOC(Cn1c(Cc2ccccc2)nnc1SC)OCC

Procedure:
In 3 ml of methanol was dissolved 0.307 g of the 3-benzyl-4-(2,2-diethoxyethyl)-4H-1,2,4-triazole-5-thione prepared in Reference Example 2, followed by addition of 0.6 ml of a 2N solution of sodium methoxide in methanol. Under stirring, 0.07 ml of methyl iodide was added dropwise and, after 30 minutes, the methanol was evaporated off. The residue was diluted with water and extracted with chloroform. The chloroform layer was washed with water, dried over Na2SO4. Evaporation of the solvent gave 3-benzyl-4-(2,2-diethoxyethyl)-5-methylthio-4H-1,2,4-triazole as an oil (quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8](O)(=[O:10])=[O:9])[CH:7]=1.O=S(Cl)[Cl:17]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([Cl:17])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1

Procedure:
In a similar fashion using route 39 general procedure 96, 5-methyl-2-nitro-benzenesulfonic acid 449 (1.8 g, 8.2 mmol), SOCl2 (10 ml) and DMF (0.18 ml) at 90° C. for 3 h gave the title compound (1.2 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[CH3:8])=[CH:4][F:5].[FH:15]>>[F:1][C:2]([F:13])([F:14])[CH:3]([C:6]([F:11])([F:12])[C:7]([F:10])([F:9])[CH3:8])[CH:4]([F:15])[F:5]
Reactant: CC(F)(F)C(F)(F)C(=CF)C(F)(F)F
Reactant: F
Product: CC(F)(F)C(F)(F)C(C(F)F)C(F)(F)F

Procedure:
As another example, 4-difluoromethyl-2,3,3,5,5,5-hexafluoro-1-pentene may be prepared by fluorinating commercially available 2,3-pentanedione to form 2,2,3,3-tetrafluoropentane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-pentene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-pentene to form 2-trifluoromethyl-1,3,3,4,4-pentafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoropentane which may then be dehydrohalogenated to form 4-difluoromethyl-2,3,3,5,5,5-hexafluoro-1-pentene.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=1)=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)c2ccc(Cl)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.9 %

Procedure:
In a 50 mL round-bottomed flask, 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester hydrochloride (intermediate I) (0.30 g, 0.791 mmol) and 4-chlorobenzoyl chloride (138 mg, 0.791 mmol) were added at 0° C. to 15 mL CH2Cl2. The reaction was stirred at 0° C. for 5 min. and then N,N-diisopropylethylamine (511 mg, 3.96 mmol) was added. The reaction mixture was stirred at 0° C. for 1 hr. The mixture was concentrated to dryness and then purified by flash chromatography using 40% ethyl acetate-hexanes. The desired product 7-chloro-3-[(4-chloro-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (171 mg, 45%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1(F)[CH2:6][NH:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1>C1COCC1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1
Reactant: COC(=O)[C@H]1CC(F)(F)CN1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c[nH]1
Temperature: 70 °C
Yield: 56.5 %

Procedure:
To solution of (R)-methyl 4,4-difluoropyrrolidine-2-carboxylate (2.00 g, 12.11 mmol) in THF (40 mL) was added manganese dioxide (8.42 g, 97 mmol) and the resulting mixture was heated at reflux (oil bath temp ˜70° C.) for 3 h. After cooling to rt, the reaction mixture was filtered through a pad of Celite, rinsed with additional THF (20 mL×4), and DCM (40 mL×4) and the resulting filtrate was concentrated under vacuum to afford a dark brown oil as the crude product which was purified via flash silica gel chromatography (eluent: CH2Cl2/MeOH, O-10%) to afford 0.98 g (56%) of the title compound as a white solid. HPLC (condition B): retention time=1.71 min. LCMS (condition B): m/z 144+ve. 1H NMR (400 MHz, MeOD) δ ppm 6.81 (1 H, dd, J=3.63, 1.87 Hz), 6.59 (1 H, d, J=1.32 Hz), 3.86 (3 H, s).