Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]([NH2:7])=[NH:6].C([O:10][C:11](=O)[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O)C.O>CN(C=O)C>[OH:10][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:4]=[C:5]([NH2:7])[N:6]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(O)cc(-c2ccc(F)cc2)n1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Into an oven-dried three neck round bottom, equipped with reflux condenser and nitrogen inlet, and two addition funnels with stoppers, were added oven-activated 5 Å molecular sieves under a stream of dry nitrogen. Sodium hydride (95%) 3.03 grams (0.126 mole) was added to the room temperature flask followed by 40 mL of dry DMF. Stirring was initiated to achieve a suspension of the solids. A solution of guanidine hydrochloride, 11.9 grams (0.125 mole) dissolved in 40 mL of dry DMF was added dropwise via addition funnel over 0.25 hours and stirring was continued for 0.5 hours at room temperature. 3-(4-Fluorophenyl)-3-oxo-propionic ethyl ester, 26.28 grams (0.125 mole) was dissolved in 75 mL of dry DMF and added to the reaction flask via dropper funnel over 0.25 hours. The mixture was then heated at reflux overnight. The mixture was filtered hot and concentrated to afford a heterogeneous mixture. Water, 100 mL, was added and a solid that formed was filtered off and dried. The solid was recrystallized from methanol to afford 4-hydroxy-6-(4-fluorophenyl)pyrimidin-2-amine (51% yield). Hydroxy-pyrimidine compounds were used in the procedure of Method G.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:16])([C:14]#N)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OCC)(=[O:19])C.CCCCCC.C[OH:30]>Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:16])([C:14]([O:19][CH3:17])=[O:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Reactant: CO
Agent: Cl
Solvent: CCCCCC
Product: COC(=O)C1(O)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-hydroxy-4-piperidinecarbonitrile (30.0 g, 118 mmol) in methanol (590 mL) and concentrated HCl (590 mL) was heated at reflux for 18 hours. The product was obtained following chromatography (SiO2, ethyl acetate:hexane, 1:4). MS (EI, M+H)+ 250.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]1[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH:11]1[CH3:12]>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:10]1[O:20][C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:16][CH2:15]2)[O:13][CH:11]1[CH3:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC1COC2(CCNCC2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1COC2(CCN(c3ccc(C#N)cc3)CC2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-fluorobenzonitrile (1.22 g, 10.0 mmol) and 4-piperidone propylene ketal (2.02 g, 12.85 mmol) was stirred at room temperature overnight. The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6 mm, 10% EtOH-90% CHCl3) afforded the title compound (34).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](#[N:18])[CH:16]=[CH2:17].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:17][CH2:16][C:15]#[N:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CCCOc1ccc(Oc2ccccc2)cc1
Yield: 34.6 %

Procedure:
3-(p-Phenoxyphenoxy)propionitrile was prepared by heating under reflux for 18 hours a mixture of 25 g of p-phenoxyphenol, 28.4 g of acrylonitrile and 5 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol. It was worked up by cooling, diluting with 400 ml water, extracting using ethyl acetate; washing the organic layer with 5% aqueous sodium hydroxide, drying, evaporating the solvent, and recrystallizing from hexane to yield 11.1 g of 3-(p-phenoxyphenoxy)propionitrile m.p. 81-3° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([CH2:17][O:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([OH:27])[C@H:22]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][O:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:20])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H](O)[C@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CCCN(C(=O)OCc2ccccc2)C1c1ccccc1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
Dimethyl sulfoxide (9.1 mL, 10.0 g, 128.6 mmol) in dichloromethane (50 mL) was added slowly to a cooled (-75° C.) solution of oxalyl chloride (6.9 mL, 10.2 g, 80.4 mmol) in dichloromethane (500 mL). The mixture was stirred at -75° C. for 15 min., then (2R,3R)-1-(phenylmethoxycarbonyl)-2-phenylpiperidin-3-ol (Description 79, 20.0 g, 64.3 mmol) was added slowly. The mixture was stirred at -75° C. for 1 h., then triethylamine (27 mL, 19.5 g, 192.9 mmol) was added. The mixture was stirred at -75° C. for 1 h., then at room temperature overnight. The mixture was washed with aqueous citric acid (1M), aqueous sodium hydrogen carbonate, water, and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (19.56 g, 98%). 1H NMR (250 MHz, CDCl3) δ7.39-7.20 (10 H, m), 5.74 (1 H, br s), 5.17 (2 H, br s), 4.13 (1 H, br s), 3.40 (1 H, br m), 2.47 (2 H, m), and 1.94 (2 H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[O:27]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][N:28]([C:26]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])=[O:27])[CH2:33][CH2:32]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 68.5 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (4.43 g, 18.79 mmol), N,N-diisopropylethylamine (4.68 ml, 26.84 mmol) and 4-dimethylaminopyridine (0.33 g, 2.68 mmol) were added to a suspension of tert-butyl 4-chlorocarbonylpiperazine-1-carboxylate (3.34 g, 13.42 mmol) in toluene (70 ml), and the resulting mixture was stirred at 100° C. for 4.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/methylene chloride/ethyl acetate=45/45/10) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-tert-butoxycarbonylpiperazine-1-carboxylate (4.12 g, yield 69%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:25]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26]1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:30]([C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1ccoc1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 3-furansulfonyl chloride (43 mg, 0.256 mmol), the title compound was obtained as a white solid (71 mg, 61% yield). MS (ESI): 474.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[C:20]([CH3:23])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]#[C:25]Br.C1COCC1.C(=O)([O-])O.[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([CH3:23])=[C:21]3[N:22]=[C:25]2[NH2:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1N
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc2c1nc(N)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
A mixture of N2-[4-(benzyloxy)phenyl]-4-methylpyridine-2,3-diamine (8.70 g), cyanogen bromide (6.04 g), THF (80 ml) and water (20 ml) was stirred at room temperature for 24 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate, treated with activated carbon, and recrystallized from methanol to give the title compound (5.60 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([NH:18][CH2:19][CH3:20])=[N:13][C:14]([F:17])=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5]([Br:21])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>N1C=CC=CC=1>[Br:21][C:5]1[CH:4]=[N:3][C:2]2[N:18]([CH2:19][CH3:20])[C:12]3[N:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=3[NH:10][C:8](=[O:9])[C:7]=2[CH:6]=1
Reactant: CCNc1nc(F)ccc1NC(=O)c1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCN1c2nc(F)ccc2NC(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a solution of the 2-chloro-N-{2-(ethylamino)-6-fluoro-3-pyridinyl}-5-bromo-3-pyridinecarboxamide (73.5 g, 216 mmol) in pyridine (435 mL) at 50° C. was added drop-wise a 1 M solution of NaHMDS in THF (520 mL, 520 mmol). After 10 min, the reaction was allowed to cool to room temperature, then poured over ice water (2 L). The resulting solid was filtered, rinse with water and then hexane. The solid was dried under reduced pressure to give the title compound (50.6 g, 69% yield) as a dark green solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:19])[C@H:5]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH2:6].C(N(CC)CC)C.[NH:27]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[C@H:28]([C:41](ON1C(=O)CCC1=O)=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C)C=O>[NH:27]([C:51]([O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:52])[C@H:28]([C:41]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35]
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cold solution of Nε -t-butyloxycarbonyl-L-lysine methyl ester hydrochloride (H-Lys(Boc)-OMe.HCl) (0.89 g, 3 mmoles) and triethylamine (0.46 ml, 3.3 mmoles) in dimethyl-formamide (8 ml) is added Nα -benzyloxycarbonyl-Nε -t-butyloxy-carbonyl-L-lysine N-hydroxysuccinimide ester (Z-Lys(Boc)-OSu) (1.43 g, 3 mmoles) (Bull. Chem. Soc. Japan 39, 882 (1966)) and the mixture is allowed to stand at 4° C overnight followed by evaporation in vacuo at a bath temperature of 40° C. The residue is dissolved in ethyl acetate and the solution is washed successively with ice-cold M hydrochloric acid, water, and M sodium bicarbonate, dried over magensium sulfate and evaporated in vacuo to give a residue, which is precipitated from ethyl acetate-petroleum ether. Reprecipitation from the same solvent yields the desired product in pure form; yield 1.80 g (96.5%), [α]D22.5 -11.7°±0.5° (c 1.0, methanol). Thin-layer chromatography (silica gel): homogeneous (to ninhydrin after pretreatment with hydrobromic acid) in chloroform-methanol-acetic acid (90:10:3, v/v).
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[N:29]=[CH:28][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=1)[N:13]=3.C(O)(C(F)(F)F)=O>>[CH:25]([N:21]1[C:20]([C:14]2[N:13]=[C:12]3[C:11]4[CH:28]=[N:29][C:8]([NH2:7])=[CH:9][C:10]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:24][CH:23]=[N:22]1)([CH3:27])[CH3:26]
Reactant: COc1ccc(CNc2cc3c(cn2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N)cc1OCC2
Yield: 54.8 %

Procedure:
A solution of (3,4-dimethoxy-benzyl)-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-amine (378 mg, 0.82 mmol) and TFA (15 mL) was heated at 40° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue loaded onto an SCX-2 cartridge, washing with methanol and eluting with 2M ammonia in methanol. Basic fractions were combined and then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 453 as a white solid (140 mg, 55% total). LCMS: RT=2.09 min, [M+H]+=312. 1H NMR 400 MHz (DMSO-d6) δ: 8.93 (1H, s), 7.88 (1H, s), 7.80 (1H, s), 6.19 (2H, br, s), 5.98 (1H, s), 5.90-5.88 (1H, m), 4.49-4.43 (4H, m), 1.47 (6H, d, J=6.61 Hz)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:5][C:4]=1[F:20])#[CH:2].C(NC(C)C)(C)C.I[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2>CN(C=O)C.[Cu](I)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>[F:20][C:4]1[CH:5]=[C:6]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2
Reactant: Ic1ncnc2nc[nH]c12
Reactant: C#Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(=O)NCC1CN(c2ccc(C#Cc3ncnc4nc[nH]c34)c(F)c2)C(=O)O1
Temperature: 60 °C

Procedure:
To a suspension of Example 3B (100 mg) and diisopropylamine (0.25 mL) in degassed DMF (1 mL) was added sequentially 6-iodopurine (89 mg), copper iodide (3.5 mg) and tetrakis(triphenylphosphine)palladium (21 mg). The mixture was heated to 60° C. for 4 hours. Next, the reaction mixture was cooled to room temperature and concentrated. The resultant material was dissolved in dichloromethane (4 mL), then filtered. The precipitate was washed with water (10 mL), then cold acetone (3 mL) to provide the desired solid. MS (ESI(+)) m/e 395 (M+H)+; 1H NMR (300 MHz, DMSO) δ 8.91 (s, 1H), 8.69 (s, 1H), 8.25 (t, J=5.7 Hz, 1H), 7.89 (m, 1H), 7.82 (t, J=9 Hz, 1H), 7.7 (dd, J=2.1, 12.3 Hz, 1H), 7.5 (dd, J=2.1, 9 Hz, 1H), 4.78 (m, 1H), 4.19 (t, J=9 Hz, 1H), 3.8 (dd, J=6.3, 9.6 Hz, 1H), 3.44 (t, J=5.7 Hz, 2H), 1.84 (s, 3H).
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>O1CCCC1.C1(C)C=CC=CC=1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: CSCC=COC(C)=O
Reactant: COC(=O)C(CCSC)OC(C)=O
Agent: [C]=O
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, pure E isomer, and 2.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. No catalyst was added. Toluene was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that no 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced and that no 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced. 0.16 mmoles of acrolein and 0.0294 mmoles of CH3SCH2H2CHO were the only detectable products.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[O:19])C(F)(F)F)=[C:4]1[CH3:20])[CH3:2].[OH-:21].[K+].Cl>C(O)C.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:19])=[O:21])=[C:4]1[CH3:20])[CH3:2]
Reactant: CCn1c(C)c(C(=O)C(F)(F)F)c2ccc(OC)cc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCn1c(C)c(C(=O)O)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of 1-(1-ethyl-6-methoxy-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone 71b (580 mg, 2.03 mmole) in 10 ml ethanol was added a solution of KOH (1.1 g, 20 mmole) in 10 ml water. The mixture was heated to reflux for 1 hour and cooled to room temperature. Concentrated HCl was added to adjust pH to 1. The mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was further purified by column chromatography (eluting with 1–2% MeOH in CH2Cl2) to give 350 mg product as brown solid (74% yield). 1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J=8.7 Hz), 6.90 (1H, dd, J=2.2, 8.7 Hz), 6.80 (1H, d, J=2.2 Hz), 4.14 (2H, q, J=7.2 Hz), 3.88 (3H, s), 2.77 (3H, s), 1.37 (3H, t, J=7.2 Hz).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH3:24])[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=3)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.O1CCCC1.[OH-].[Na+]>O>[CH2:10]1[C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH3:24])[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=3)=[CH:15][C:8]=2[CH2:7][CH2:6][NH:5][CH2:11]1
Reactant: CNc1nc(Nc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)ncc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(Nc2ccc3c(c2)CCNCC3)ncc1[N+](=O)[O-]

Procedure:
650 mg of 2-(3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl-amino)-4-methylamino-5-nitro-pyrimidine, 20 ml tetrahydrofuran, 10 ml water and 3.2 ml of 1N sodium hydroxide solution are stirred for 2 hours at ambient temperature and then the reaction mixture is combined with 100 ml of water. The solid precipitated is suction filtered and dried.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH3:26])[CH:21]=CC(S(O)(=O)=O)=C[CH:17]=1.[C:27]([O-])([O-:29])=[O:28].[K+].[K+].Cl>O1CCOCC1.CCOCC.O>[C:16]([O:29][C:27]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]1)=[O:28])([CH3:26])([CH3:21])[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Temperature: 60 °C

Procedure:
Place 100 g of 4-phenylpiperidine-4-carboxylic acid and p-toluenesulphonic acid in 800 ml of dioxane, add 150 ml of water and 109.7 g of K2CO3. Heat to 60° C. then add, drop by drop, 60.7 g of (Boc)20 in 100 ml of dioxane. Leave for 4 hours with stirring at 60° C. then heat under reflux for 1 hour. Evaporate to dryness, take up the solid formed in water, acidify to a pH of 3 by the addition of 2 N HCl, then add ether. Filter the crystals formed, wash them in water then in ether. Evaporate the etherified filtrate to dryness, take up the residue in ether and filter the crystals formed and add to those already obtained in order to dry them. 71 g of the desired compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]2[C:10]=1[S:9][N:8]=[N:7]2.C1C(=O)N([I:19])C(=O)C1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([I:19])[C:5]([NH2:11])=[C:6]2[C:10]=1[S:9][N:8]=[N:7]2
Reactant: Nc1ccc(Br)c2snnc12
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: Nc1c(I)cc(Br)c2snnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A mixture of 7-bromo-1,2,3-benzothiadiazol-4-amine (80.0 mg, 0.348 mmol) and NIS (117.3 mg, 0.522 mmol) in THF (6 ml) was stirred at RT overnight. The solution was adsorbed onto silica gel and purified by ISCO chromatography (10 to 30% EtOAc:heptane) to afford 95 mg (77%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 6.89 (s, 2 H), 8.05 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17]SC)[O:9]2)=[CH:4][C:3]=1[CH2:20][C:21]1[S:22][C:23]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)=[CH:24][N:25]=1.Cl[C:32]1C=C(C=CC=1)C(OO)=O.[S:42]([O-:46])([O-])(=[O:44])=S.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][S:42]([CH3:32])(=[O:46])=[O:44])[O:9]2)=[CH:4][C:3]=1[CH2:20][C:21]1[S:22][C:23]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)=[CH:24][N:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)C[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 66 %

Procedure:
The solution of methyl sulfide 92 (175 mg, 0.37 mmol) and meta-chloroperoxybenzoic acid (210 mg 0.93 mmol) in CH2Cl2 (3.7 mL) was stirred at 0° C. for 1 h. To the reaction solution was added to sodium thiosulfate solution, and the resulting mixture was extracted with CH2Cl2. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous MgSO4. The drying agent was filtered off, and evaporated under reduced pressure. The residue was purified by prep HPLC (C18) to afford the titled compound methylsulfone 93 (121 mg, 66%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:25][CH2:24][CH2:23][Cl:22])[C:6]=2[CH:12]=1
Reactant: ClCCCI
Reactant: CCc1c(Cl)cc2c(c1Cl)OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCc1c(Cl)cc2c(c1Cl)OCC(=O)N2CCCCl
Yield: 67.1 %

Procedure:
6,8-Dichloro-7-ethyl-4H-benzo[1,4]oxazin-3-one (95MF46) (0.342 g, 1.39 mmol), Cs2CO3 (0.678 g, 2.08 mmol) and 3-chloro-1-iodopropane (0.313 g, 1.52 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF52(2226)) (0.301 g, 67%). 1H NMR (CDCl3) δ 7.01 (s, 1H), 4.68 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H), 2.91 (q, J=7.6 Hz, 2H), 2.10-2.18 (m, 2H), 1.16 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) δ 163.8, 140.6, 135.8, 127.9, 127.7, 123.6, 113.8, 67.9, 42.2, 39.3, 30.0, 24.7, 12.7.