Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]=[CH:13][S:12][C:10]3=2)[NH:5][C:4]1=[O:15].C(O)(=O)C>C1COCC1.[Zn]>[S:12]1[C:10]2=[C:11]3[C:6](=[CH:7][CH:8]=[C:9]2[N:14]=[CH:13]1)[NH:5][C:4](=[O:15])[CH2:3]3
Reactant: CSC1C(=O)Nc2ccc3ncsc3c21
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1Cc2c(ccc3ncsc23)N1
Temperature: 60 °C
Yield: 69.7 %

Procedure:
A 2-L three-neck round bottom flask was fitted with an internal thermometer, 250-mL addition funnel, magnetic stir bar and septa. The flask was charged with nitrogen, 200 mL of dry THF, and 6-aminobenzothiazole (15.2 g, 0.100 mol). The mixture was stirred and cooled in a dry ice-acetone bath to an internal temperature of −74° C. A solution of tert-butyl hypochlorite (11.0 g, 0.103 mol) in 50 mL of dichloromethane was added over a 15 minute period. The resultant solution was stirred for an additional 3 hours at dry ice-acetone bath temperature. To the reaction was then added by slow, dropwise addition a solution of ethyl methylthioacetate (13.8 g, 0.103 mol) in 50 mL of dichoromethane. The resultant solution was stirred for an additional 3 hours at dry ice-acetone bath temperature. A solution of triethyl amine (25.3 g, 0.250 mol) and 50 ml of dichloromethane was added at dry ice-acetone bath temperature, and the solution was stirred for 0.5 hours. The cooling bath was removed, and the reaction was allowed to warm to room temperature. The reaction was then concentrated to a thick residue. The thick oil was resuspended in 200 mL of ether and 600 mL of 0.25 M hydrochloric acid. The mixture was allowed to stir for 24 h. The resulting solid was filtered from the mixture and triturated with water and ether. The solid was then resuspended in cold MeOH, filtered and dried under vacum for 16 hours to yield 18.7 g (79%) of 8-(methylsulfanyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one: 1H NMR (DMSO-d6)δ 10.8 (s, 1H), 9.2 (s, 1H), 8.0 (d, 1H), 7.1 (d, 1H), 1.8 (s, 3H); APCI-MS m/z 235 (M-H). To a 500-mL Erlenmeyer flask was added a stir bar, 8.1 g (0.034 moles) of 8-(methylsulfanyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one and 100 mL of glacial acetic acid. The mixture was stirred until all the starting material had dissolved. The reaction mixture was then diluted with 100 mL of THF. Zinc metal (16 g, 325 mesh) was then added. The heterogeneous mixture was then stirred and heated to 60° C. for 2.5 hours. The mixture was vacuum filtered through a one half-inch pad of celite. The residue on the filter pad was washed with additional THF. The filtrates were combined and concentrated to a wet solid. The solid was triturated with MeOH, filtered and air dried to yield 4.51 g (70%) of the compound as a free-flowing solid: 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 9.1 (s, 1H), 7.9 (d,;1H), 7.0 (d, 1H), 3.6 (s, 2H); APCI-MS m/z 191 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[S:5][C:4]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)=[N:3]1.[H-].[Li+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:3]1[C:2](=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[S:5][C:4]1=[N:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Product: CCOC(=O)c1ccc(N=c2sc3ncccc3c(=O)n2Cc2ccccc2)cc1

Procedure:
The reaction procedure of Example 11 was followed except that 1.31 g of ethyl 4-[(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]benzoate, 36 mg of lithium hydride and 0.48 ml of benzyl bromide were used. As a result, 1.28 g of ethyl 4-[(3-benzyl-4-oxo-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-2-ylidene)amino]benzoate was obtained as a low polarity substance, and 20 mg of ethyl 4-[N-benzyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]benzoate was obtained as a high polarity substance.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:9]=1[CH2:10]Br.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:10][C:9]1[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:8]=1[F:7])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: Fc1ccc(Br)cc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCOCc1cc(Br)ccc1F
Temperature: -40 °C

Procedure:
In a 25 ml flask 4-(t-butoxycarbonylamino)butanol was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. The solution was cooled to −40° C. and potassium tert-butoxide (1M in tetrahydrofuran, 2.14 ml, 2.14 mmol) was added slowly. The resulting mixture was stirred at −40° C. for thirty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (521 mg, 1.94 mmol), added dropwise as a solution in tetrahydrofuran (3.5 ml). The resulting mixture was slowly warmed to 0° C. and stirred at this temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]#[CH:4].[OH:10][CH2:11][C:12]1([CH2:16][CH2:17][CH3:18])[CH2:15]O[CH2:13]1>>[CH2:1]([O:5][CH2:6][C:7]12[O:10][CH2:11][C:12]([CH2:16][CH2:17][CH3:18])([CH2:15][O:9]1)[CH2:13][O:8]2)[CH2:2][C:3]#[CH:4]
Reactant: CCCC1(CO)COC1
Reactant: C#CCCOCC(=O)O
Product: C#CCCOCC12OCC(CCC)(CO1)CO2

Procedure:
1-(But-3-ynyloxymethyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 2-(but-3-ynyloxy)acetic acid and 3-hydroxymethyl-3-n-propyl-oxetane using methodology described in Example I
Reaction SMILES: F[CH2:2][C:3](O)([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[CH3:10])C(F)(F)F.CC(=O)C(=O)CC>>[F:11][C:9]([F:12])([C:8]([F:14])([F:13])[CH2:3][CH3:2])[CH3:10]
Reactant: CC(F)(F)C(F)(F)C(O)(CF)C(F)(F)F
Agent: CCC(=O)C(C)=O
Product: CCC(F)(F)C(C)(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-pentanol 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 sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-pentanol.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(O[C:26](C)([CH3:28])[CH3:27])=O.ICCC.C(O)(C(F)(F)F)=O>>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:27][CH2:26][CH3:28])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCI
Product: CCCOc1ccc(C[C@@H]2CNCCO2)cc1Br

Procedure:
Example 63 was prepared using the same procedure as described for example 4, starting from N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a), and 1-iodopropane. The resulting intermediate was deprotected with TFA as described for example 4 to yield the desired morpholine example 63 as a colorless oil (27 mg, 64% over 2 steps) after purification by HPLC.
Reaction SMILES: COC(C1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH3:26])[C:17]([CH3:28])([CH3:27])[CH:16]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=O.C(N1C2C(=CC=CC=2)C(CS(Cl)(=O)=O)=CC1(C)C)C.C(NCC)C.C(Cl)(Cl)Cl>C(O)C>[CH2:9]([N:8]([CH2:7][CH3:6])[S:11]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][CH3:26])[C:17]([CH3:27])([CH3:28])[CH:16]=1)(=[O:12])=[O:13])[CH3:10]
Reactant: CCN1c2ccccc2C(CS(=O)(=O)N2CCC(C(=O)OC)CC2)=CC1(C)C
Agent: CCN1c2ccccc2C(CS(=O)(=O)Cl)=CC1(C)C
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Solvent: CCO
Product: CCN1c2ccccc2C(CS(=O)(=O)N(CC)CC)=CC1(C)C
Yield: 79 %

Procedure:
N,N-diethyl-(1-ethyl-2,2-dimethyl-1,2-dihydroquinol-4-yl)-methanesulfon-amide (11) is prepared similarly to compound (10) using compound (9) with diethylamine. The product is isolated by column chromatography on silica gel with a gradient running from chloroform to ethanol.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[O-]S([O-])=O.[Na+].[Na+].[OH-].[Na+].CC(C)=O>O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:13]([OH:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1S(=O)O

Procedure:
10.7 g (0.04 mol) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfonyl chloride are introduced into a solution of 15 g of Na2SO3 and 4 g of NaOH in 100 ml of water. After adding a little acetone, the mixture is heated on a steam bath for 30 minutes, then filtered and the pH is adjusted to 2-3 with concentrated hydrochloric acid.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([CH:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([F:25])=[CH:19][C:18]=2[O:26][CH3:27])[CH2:14][CH:15]=[CH2:16])[C:9](=[O:12])C=C)[CH:2]=1>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH:13]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([F:25])=[CH:19][C:18]=3[O:26][CH3:27])[CH2:14][CH:15]=[CH:16][C:9]2=[O:12])[CH:2]=1
Reactant: C=CCC(c1c(OC)cc(F)cc1OC)N(Cc1cccc(-c2ccccc2)c1)C(=O)C=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: [Ti+4]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: COc1cc(F)cc(OC)c1C1CC=CC(=O)N1Cc1cccc(-c2ccccc2)c1
Temperature: 50 °C

Procedure:
A yellow solution of N-([1,1′-biphenyl]-3-ylmethyl)-N-(1-(4-fluoro-2,6-dimethoxyphenyl)but-3-en-1-yl)acrylamide (152 mg; 0.34 mmol; 1.0 equiv.) in anh. DCM (17 ml) was treated with titanium(IV) isopropoxide (0.20 ml; 0.68 mmol; 2.0 equiv.), and the mixture was heated to 50° C., under nitrogen, for 1 h. Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (11.3 mg; 0.04 equiv.) was then added, and the resulting mixture was further heated at reflux for 20 h. Subsequent concentration to dryness under reduced pressure, and purification by FC (DCM/MeOH=50/1) afforded 1-([1,1′-biphenyl]-3-ylmethyl)-6-(4-fluoro-2,6-dimethoxyphenyl)-5,6-dihydropyridin-2(1H)-one as a pale yellow foam. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 417.76 g/mol.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[N:14]([N:23]=[C:24]([CH3:26])[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[N:14]([NH:23][CH:24]([CH3:25])[CH3:26])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(C)=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 233A (0.044 g, 0.11 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran 0.085 mL, 0.17 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.99 (m, 6 H) 3.94 (m, 1 H) 5.65 (d, J=4.41 Hz, 1 H) 7.04 (t, J=7.35 Hz, 1 H) 7.28 (m, 2 H) 7.51 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.75 (d, J=8.46 Hz, 1 H) 8.06 (dd, J=8.09, 1.47 Hz, 1 H) 16.28 (s, 1 H). (ESI−) m/z 397 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][N:13]=[N+]=[N-])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][NH2:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CN=[N+]=[N-])CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)C(CN)CC2

Procedure:
20 g (0.1 mol) of 6-methoxyindan-1-ylmethylazide are dissolved in 400 ml of diethyl ether and added dropwise, at 25-30° , to a suspension of 5.0 g (0.13 mol) of lithium aluminium hydride in 200 ml of diethyl ether. When the addition has been completed, the mixture is maintained under reflux for 6 hours and, while cooling with ice, 5 ml of water, 5 ml of 15% sodium hydroxide solution and 15 ml of water are added thereto. The white precipitate which has formed is filtered off and boiled up 3 times with dichloromethane. The organic filtrates are combined, dried over magnesium sulphate and concentrated to dryness by evaporation in vacuo. The N-(6-methoxyindan-1-ylmethyl)amine which is obtained as an oily residue is converted into the hydrochloride with ethereal hydrochloric acid and recrystallised from isopropanol/diethyl ether. The pure 6-methoxyindan-1ylmethylammonium chloride melts at 129°-131°.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[OH:25].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].N1C=CC=CC=1>ClCCl>[F:26][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C(=O)Cl
Reactant: Cn1nc(C(F)(F)F)c(-c2c(O)c3nccnc3[nH]c2=O)c1OC(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)Oc1c(-c2c(C(F)(F)F)nn(C)c2OC(F)F)c(=O)[nH]c2nccnc12

Procedure:
7-(5-Difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (Example 2.6) (0.34 g), isobutyryl chloride (0.11 ml), and pyridine (0.10 ml) were stirred in dichloromethane (10 ml) at ambient temperature for 2 hours. The reaction mixture was washed successively with aqueous hydrochloric acid (1M), aqueous sodium hydrogen carbonate (saturated) and water. The organic fraction was dried over sodium sulfate and concentrated to give Compound No. B23 of Table B (0.335 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18]>C1C=CC=CC=1>[CH3:12][C:4]1[C:3]([N+:13]([O-:15])=[O:14])=[C:2]([C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[CH3:11])[N:19]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17][CH3:18]
Reactant: CCCNCCC
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: c1ccccc1
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
Five grams of 1-chloro-3,4-dimethyl-2,6-dinitrobenzene and 5.05 grams of di-n-propylamine are dissolved in benzene and the mixture is refluxed. The benzene is then removed from the mixture by boiling and toluene is added to the remaining residue. The thus-formed mixture is then refluxed, filtered, and the filtrate stripped in vacuo. The residue is treated with hexane and the mixture chilled in dry ice and acetone. The solid from the mixture is collected and dried, it has a melting point of 42° C. to 43.5° C. and is the desired product.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([N:1]1[CH2:2][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:4]1)=[O:27]
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (330 mg, 1.39 mmol) and Na2CO3 (590 mg, 5.56 mmol) in dichloromethane (10 ml) at 0° C. was added chloroacetyl chloride (107 μl, 1.39 mmol). After 10 mins the reaction temperature was raised to RT and stirred for a further hour. The reaction was then filtered and concentrated at reduced pressure to give the title compound as colourless oil (411 mg, 91% yield), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Cc1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Cl)c1
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-methylphenyl isocyanate (0.60 ml, 5.01 mmol) in THF (20 ml) was added Et3N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-methylphenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-[N′-(2-methylphenyl)ureido]phenylacetate (1.23 g, 74%) as a colorless powder. 1H-NMR (CDCl3) δ2.34 (s, 3H, 3.54 (s, 2H), 3.68 (s, 3H), 6.24 (br, 1H), 6.99 (br, 1H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 7.21-7.31 (m, 5H), 7.44 (d, J=7.6 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H); MS (ESI) m/z 333 (M++1), 335 (M++3).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:45]([Cl:56])=[CH:44][C:43]=1[C:57](=[O:59])[CH3:58])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:45]([Cl:56])=[CH:44][C:43]=1[C:57](=[O:59])[CH2:58][Br:1])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: [Br-]
Reactant: CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 53.1 %

Procedure:
Phenyltrimethylammonium tribromide (7.5 g, 0.02 mol) was added portionwise to a stirred solution of 1-(2,4-Bis-benzyloxy-5-chloro-phenyl)-ethanone (7.09 g, 0.019 mol) in tetrahydrofuran (100 ml) and the mixture was stirred for 2 h. The mixture was partitioned between water (100 ml) and diethyl ether (2×50 ml). The combined organic phases were dried over magnesium sulphate and concentrated to give a beige solid. Crystallisation from toluene (100 ml) gave 1-(2,4-Bis-benzyloxy-5-chloro-phenyl)-2-bromo-ethanone as a white solid (4.5 g)
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([NH:11][CH:12]([O:23][CH3:24])[N:13]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([NH2:25])[N:8]=1)=[O:6].Cl>CO>[NH2:25][C:9]1[N:8]=[C:7]([C:5]([OH:6])=[O:4])[N:15]=[C:14]2[C:10]=1[NH:11][CH:12]([O:23][CH3:24])[N:13]2[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(N)c2c(n1)N(Cc1ccccc1)C(OC)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC1Nc2c(N)nc(C(=O)O)nc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
2N Sodium hydroxide (500 μl, 1 mmol) was added to a solution of methyl-6-amino-9-benzyl-8-methoxy-8,9-dihydro-7H-purine-2-carboxylate (Example 245) (100 mg, 0.32 mmol) in methanol (3 ml) and the reaction mixture stirred at room temperature for 2 hours. The solution was acidified to pH 2 with 2N hydrochloric acid and the resultant precipitate collected by filtration and washed with water. The solid was azeotroped with toluene and ether then dried in vacuo to yield the title compound (64 mg, 0.214 mmol).
Reaction SMILES: [CH3:1][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:6])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:27](I)[CH3:28].O>CN(C)C=O>[CH3:6][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:1])[C:3]([O:5][CH2:27][CH3:28])=[O:4]
Reactant: CCI
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
To a mixture of 2-methyl-2-(6-methyl-5-phenyl-2,3-dihydro-4-oxo-4H-1,3-oxazin-3-yl)-propionic acid (0.83 g) and potassium carbonate (0.45 g) in 4 ml of dimethylformamide (DMF) was added ethyl iodide (0.56 g), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica gel column to get the captioned compound (0.87 g).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[O:12][C@@H:7]1[C:8]([O:10]C)=[O:9])(=O)C.[OH-].[Na+:14]>CO.ClCCl>[Na+:14].[O:12]1[C@@H:6]([CH2:5][OH:4])[C@H:7]1[C:8]([O-:10])=[O:9]
Reactant: COC(=O)[C@H]1O[C@H]1COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C([O-])[C@H]1O[C@H]1CO
Temperature: 5 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A modification of the general procedure of Manchand, et. al. (Manchand, et al., 1988) is employed. A solution of methyl (2S,3S)-4-acetoxy-2,3-epoxybutanoate (81.8 g, 465 mmol) in methanol (450 mL) is cooled in an ice bath to 5° C. The solution is treated with solid sodium hydroxide at such a rate that the temperature remained less than 15° C. This mixture is stirred at 5° C. for 3 hours and diluted with dichloromethane (200 mL). The mixture is stirred at room temperature for 30 minutes. The solid is collected by filtration and washed with dichloromethane (200 mL). The resulting filter cake is dried in vacuo at room temperature to yield the title compound as a solid (58.8 g, 90% theoretical yield).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:8][C:9]#[CH:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>C(N(CC)CC)C.[Cu]I>[CH3:11][C:2]([CH3:1])([CH2:8][C:9]#[C:10][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#CCC(C)(C)C(=O)OCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)CC#CC(=O)C(C)(C)C
Temperature: 23 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
To a solution of ethyl 2,2-dimethylpent-4-ynoate (1.00 g, 6.5 mmol), 2,2-dimethyl-propionyl chloride (0.8 mL, 6.5 mmol), and dichlorobis(triphenylphosphine) palladium(II) (460 mg, 0.65 mmol) in triethylamine (TEA) (12 mL) is added CuI (62 mg, 0.32 mmol). The mixture is stirred at 23° C. for 3 h then partitioned between Et2O and saturated aqueous NH4Cl. The organics are washed with water, dried with MgSO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, hexanes to 10% EtOAc in hexanes) to give the title intermediate (828 mg, 54%).