Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)=[O:7])[CH3:4].[C:21]([O:25][C:26]([N:28]1[CH2:32][C@H:31]([CH3:33])OS1(=O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([C@H:31]([CH3:33])[CH2:32][NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([F:20])([F:18])[F:19])[CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2n1[C@H](C)CNC(=O)OC(C)(C)C
Temperature: 5 °C
Yield: 87.9 %

Procedure:
Sodium hydride (0.75 g, 17 mmol) was suspended in N,N-dimethylformamide (15 mL) and a solution of 6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (3.6 g, 14 mmol) in N,N-dimethylformamide (15 mL) was added with cooling at 5° C. After 1 h (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (4.0 g, 17 mmol) was added and the solution was allowed to reach room temperature over the weekend. The solution was partitioned between ice water (600 mL) and diethylether (2-×250 mL). The organic layer was washed with ice water and brine, dried (MgSO4), and evaporated. Chromatography on silica gel with n-hexane/diethylether (4:1) yielded the title product as yellow oil (5.1 g, 88%). ISP-MS: m/e=415.3 (M+H+), αD20=−29.6
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=O.Cl.[NH2:25][OH:26].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=[N:25][OH:26]
Reactant: NO
Reactant: CSc1ccc(/C=C2/C(C)=C(CC=O)c3cc(F)ccc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSc1ccc(/C=C2/C(C)=C(CC=NO)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the acetaldehyde derivative from Step 2 (3.3 g, 10.18 mmol), hydroxylamine hydrochloride (1.42 g, 20.4 mmol), ethanol (25 mL) and triethylamine (2.06 g, 20.4 mmol) was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The crude product from the organic phase was purified by column chromatography on silica gel using a 1:2 mixture of ethyl acetate:hexane as eluent. The title compound was obtained as a yellow solid, mp: 146-150° C.
Reaction SMILES: CN(C)C=O.CS(O[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.O.O.[CH3:22][N:23]([CH3:27])[C:24](=[S:26])[S-:25].[Na+]>O>[CH3:22][N:23]([CH3:27])[C:24](=[S:25])[S:26][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:17])[F:18]
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Reactant: CN(C)C(=S)[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCCCSC(=S)N(C)C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To 100 ml of N,N-dimethylformamide, 4.56 g (20 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 4.70 g (26 mmol) of sodium dimethyldithiocarbamate dihydrate were dissolved, followed by stirring at 100° C. for 3 hours. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 2.60 g (yield: 51%) of 6,6-difluoro-5-methyl-5-hexenyl N,N-dimethyldithiocarbamate.
Reaction SMILES: C=O.[CH2:3]([C:5]([CH2:10][OH:11])([CH2:8][CH3:9])[CH:6]=[O:7])[OH:4]>>[CH2:3]([C:5]([CH2:10][OH:11])([CH2:6][OH:7])[CH2:8][CH3:9])[OH:4]
Reactant: CCC(C=O)(CO)CO
Agent: C=O
Product: CCC(CO)(CO)CO

Procedure:
EP-A 860 419, too, proposes carrying out the preparation of 2,2-dimethylolbutanal from n-butyraldehyde and formaldehyde in a plurality of stages, with the actual reaction occurring in the first stage and the 2-ethylacrolein obtained as by-product being reacted with further formaldehyde in the second stage. The 2,2-dimethylolbutanal prepared in this way can then be hydrogenated to give trimethylolpropane. Once again, no formate is isolated.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[C:34]([O:38][C:39]([NH:41][C:42]([CH3:62])([CH3:61])[CH2:43][C:44]1[C:52]2[C:47](=[C:48](OS(C(F)(F)F)(=O)=O)[CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.[Cl-].[Na+].O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:34]([O:38][C:39](=[O:40])[NH:41][C:42]([CH3:62])([CH3:61])[CH2:43][C:44]1[C:52]2[C:47](=[C:48]([C:2]3[CH:10]=[CH:9][C:5]([C:6](=[O:7])[NH2:8])=[CH:4][CH:3]=3)[CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(Cc1c[nH]c2c(OS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Reactant: NC(=O)c1ccc(Br)cc1
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Cc1c[nH]c2c(-c3ccc(C(N)=O)cc3)cccc12)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 58.5 %

Procedure:
A solution of 4-bromobenzamide (150 mg, 0.75 mmol), bis(pinacolato)diboron (209 mg, 0.825 mmol), potassium acetate (0.221 g, 2.25 mmol) and {1,1′-bis(diphenylphosphino)-ferrocene} dichloropalladium dichloromethane complex (18 mg, 0.0225 mmol) in dimethylsulfoxide (5 mL) is heated to 80° C. for two hours. The mixture is cooled to 20° C. and trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (262 mg, 0.600 mmol), {1,1′-bis(diphenylphosphino)-ferrocene} dichloropalladium dichloromethane complex (18 mg, 0.0225 mmol) and sodium carbonate (1.9 mL, 2M, 3.75 mmol) are added. The mixture is heated to 80° C. overnight. The mixture is diluted with brine and ethyl acetate. The organic fraction is washed seven times with brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The residue is purified using silica gel chromatography (dichloromethane/10% methanol, 0.7M ammonia in dichloromethane gradient elution) to give 143 mg of {2-[7-(4-carbamoyl-phenyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (58%). FDMS m/e=408 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[NH:9][C:10](=[O:13])[O:11][CH3:12].CC#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:29]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([I:29])=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[NH:9][C:10](=[O:13])[O:11][CH3:12]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)Nc1c(O)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1c(O)ccc(I)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.9 %

Procedure:
To a mixture of methyl (2-fluoro-6-hydroxyphenyl)carbamate (1.06 g) and MeCN (90 mL) was added p-toluenesulfonic acid monohydrate (1.09 g), followed by stirring at room temperature for 5 minutes. To the reaction mixture was added N-iodosuccinimide (1.29 g), followed by stirring at room temperature overnight. The reaction mixture was diluted with chloroform, and washed with a 10% aqueous sodium thiosulfate solution and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=85/15-75/25) to obtain methyl (2-fluoro-6-hydroxy-3-iodophenyl)carbamate (408 mg).
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][NH:18][C:19]2[C:28]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24](B4OC(C)(C)C(C)(C)O4)[CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19]2[C:28]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:2]4[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=4[C:4]#[N:5])[CH:25]=3)[N:20]=2)=[CH:44][CH:45]=1
Reactant: Cc1cccc(C#N)c1Br
Reactant: COc1ccc(CNc2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3cc2C2CCOCC2)cc1
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CNc2nc3ccc(-c4c(C)cccc4C#N)cc3cc2C2CCOCC2)cc1
Temperature: 140 °C

Procedure:
A mixture of 2-bromo-3-methylbenzonitrile (0.744 g, 3.79 mmol), N-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.60 g, 1.265 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.121 g, 0.253 mmol), potassium phosphate, anhydrous (0.524 mL, 6.32 mmol), and Pd2(dba)3 (0.116 g, 0.126 mmol) was purged with N2 followed by the addition of degassed dioxane (2 mL) and degassed water (1.0 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction went to completion and it was filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a yellow solid as (2-(2-(4-methoxybenzylamino)-3-(tetrahydro-2H-pyran-4-yl) quinolin-6-yl)-3-methylbenzonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc(O)cc23)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Yield: 90.5 %

Procedure:
By a method similar to Preparation 20, using 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-hydroxy-1H-indole (1.25 g, 5.47 mmol) in dichloromethane (5 mL) trifluoroacetic acid (5 mL), triethylsilane (875 mL, 6.0 mmol) afforded 1.14 g (90%) of the title compound as a tan solid: mp=233-237° C.; 1H NMR (400 MHz, dmso-d6): 10.41 (br s, 1H), 8.52 (br s, 1H), 7.08 (d, 1H, J=8.0 Hz), 6.92 (d, 1H, J=2.0 Hz), 6.80 (d, 1H, J=2.0 Hz), 6.53 (dd, 1H, J=8.4, 2.0 Hz), 2.84 (br d, 2H, J=11.2 Hz), 2.63-2.50 (m, 1H), 2.19 (s, 3H), 2.08-1.97 (m, 2H), 1.85 (br d, 2H, J=12.0 Hz), 1.72-1.57 (m 2H); MS (ES+) m/e 231.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13](Br)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C2C=C(Br)SC2C1=O
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)CN1C(=O)C2C=C(c3ccc(OC)cc3)SC2C1=O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, (2-bromo-4,6-dioxo-3a,4,6,6a-tetrahydro-thieno[2,3-c]pyrrol-5-yl)-acetic acid ethyl ester, example 1-d (431 mg, 1.35 mmol), 4-methoxy-phenyl boronic acid (309 mg, 2.0 mmol), cesium carbonate (1.10 g, 3.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.14 mmol) were suspended in 8 mL of ethylene glycol dimethyl ether. The reaction mixture was heated at reflux temperature for 5 hours, cooled to room temperature, and diluted with ethyl acetate. The organic mixture was successively washed with saturated sodium bicarbonate and brine solutions. The organic fractions were dried over anhydrous sodium sulfate and concentrated to a crude solid residue, which was then purified by column chromatography, eluting the title compound from silica gel with a gradient of (5-30%) ethyl acetate in hexanes to yield 197 mg of a white solid. MS: (+) m/z 348.05 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:18]([OH:19])=[N:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[OH:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(C(C)C)C(C)C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.Cl>[Cl:1][C:2]1[C:3]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][S:31]([CH3:30])(=[O:33])=[O:32])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Oc1nc2nccnc2c(O)c1-c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Oc1c(-c2ncc(Cl)cc2Cl)c(=O)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 7-(3,5-dichloro-pyrid-2-yl)-pyrido[2,3-b]pyrazine-6,8-diol (Example 1.2) (0.20 g) and N-ethyl-diisopropylamine (0.126 g) in dry dichloromethane (15 ml) was added methane sulfonyl chloride (0.074 g). The reaction mixture was stirred at ambient temperature for one hour and then stored at ambient temperature for 16 hours. The reaction mixture was diluted with aqueous hydrochloric acid (1M). The phases were separated and the organic layer was concentrated. The residue was purified by reverse phase HPLC to give Compound No. A4 of Table A as a pale brown solid (0.055 g).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].F[C:24](F)(F)C(O)=O>CO>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([O:8][CH3:24])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Reactant: O=C(O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CO[C@H]1O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Reaction time: 2 h

Procedure:
Artemisinin (100 g.) was dissolved in dry methanol (3 ml). Added sodium borohydride (30 mg.) at −5° C. The reaction mixture was stirred for 2 hours. After completion of the reaction, trifluroacetic acid (0.5 ml) was added and the reaction mixture was stirred for 5 hours. The methylation was incompleted and after workup the artemether was purified by prep TLC to yield 46 mg (46%) pure alpha, beta artemether.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][N:6]2[C:7](=[O:9])[CH:8]=1.[I-].[Na+].C(=O)(O)[O-:18].[Na+].O>CS(C)=O>[CH2:13]([C:11]1[S:12][C:5]2=[N:4][C:3]([CH2:2][OH:18])=[CH:8][C:7](=[O:9])[N:6]2[N:10]=1)[CH3:14]
Reactant: CCc1nn2c(=O)cc(CCl)nc2s1
Reactant: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1nn2c(=O)cc(CO)nc2s1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
A mixture of 7-Chloromethyl-2-ethyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (11.48 g, 50 mmol), sodium iodide (15 g, 100 mmol, 2 equiv), sodium bicarbonate (12.6 g, 150 mmol, 3 equiv), water (25 mL) and DMSO (250 mL) was stirred and heated at 80° C. for 18 h. The volatiles were mostly removed on the rotary evaporator, then the residue treated with ethyl acetate to precipitate the salts, and the mixture filtered. The filtrate was lyophilized and chromatographed on silica gel using a gradient of ethyl acetate to 3% methanol in ethyl acetate, affording 2-ethyl-7-hydroxymethyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (4.24 g, 40%). This alcohol was dissolved in acetone (150 mL) and refluxed for 3 days with a total of 15 equivalents of MnO2, added in 3-equiv portions over this time, affording complete conversion to the corresponding aldehyde. The reaction mixture was filtered through celite, the cake washed with acetone (3×100 mL), and the filtrate concentrated in vacuo, affording the title product (2.84 g, 67%). 1H NMR (300 MHz, CDCl3): δ 1.55 (t, 3H), 3.10 (q, 2H), 6.98 (s, 1H), 9.90 (s, 1H). MS (APCI) calcd for C8H7ClN3O2S: 209.03, found (M+H+): 210.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH:19]=[CH:20][C:21](OCC)=[O:22].C(O)(C)C.Cl>C1COCC1.CCOCC.O>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH:19]=[CH:20][CH2:21][OH:22]
Reactant: CCOC(=O)C=Cc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1oc(-c2ccccc2)nc1C=CCO
Reaction time: 1.5 h
Yield: 52 %

Procedure:
Lithium aluminum hydride (480 mg, 12.6 mmol) was slurried in anhydrous THF (15 mL) and treated with dropwise addition of a solution of 3-(5-methyl-2-phenyloxazol-4-yl)-acrylic acid, ethyl ester (2.60 g, 10.1 mmol) at 0° C. The reaction mixture was stirred for 1.5 h at this temperature and then treated with dropwise addition of isopropanol (1.0 mL) followed by water (10 mL). The biphasic suspension was acidified with 0.1 N HCl (10 mL), diluted with ether (20 mL) and partitioned. The aqueous layer was extracted once with ether (15 mL) and the combined organic layers dried over MgSO4 and concentrated to provide a colorless oil (1.13 g, 52%): Rf=0.18 (50% hexanes/EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.99-8.03 (m, 2H), 7.42-7.48 (m, 3H), 6.60 (dt, 1H), 6.47 (d, 1H), 4.35 (m, 2H), 3.76 (b, 1H), 2.37 (s, 3H); MS(EI): 216 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:23][N:22]([CH3:31])[N:21]=3)=[CH:16][CH:15]=2)[CH:3]=1.[CH3:32][NH:33][CH3:34].[F-].[Cs+].C(N(C(C)C)CC)(C)C>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:32][N:33]([CH3:34])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:23][N:22]([CH3:31])[N:21]=3)=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cc(Cl)c4ccccc4n3)cc2)n1
Reactant: CNC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(COc2ccc(-c3nn(C)cc3-c3ccncc3)cc2)nc2ccccc12
Temperature: 180 °C

Procedure:
To a solution of 4-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (135 mg) in tetrahydrofuran (4 mL) was added dimethylamine (2N in methanol, 0.32 mL), cesium fluoride (5 mg), diisopropyl ethyl amine (62 mg) and tetrabutyl ammonium iodide (12 mg). The reaction mixture was heated in a microwave reactor at 180° C. with 100 W of power for 40 min. The reaction mixture was filtered through celite and concentrated. Purification via MPLC biotage chromatography, eluting with 5% methanol/1% ammonium hydroxide/methylene chloride provided the title compound (36 mg). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=6.2 Hz, 2H), 8.04 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.62 (m, 1H), 7.56 (s, 1H), 7.42 (m, 1H), 7.38 (d, J=9.1 Hz, 2H), 7.15 (d, J=6.2 Hz, 2H), 7.01 (m, 3H), 5.29 (s, 2H), 3.95 (s, 3H), 3.03 (s, 6H); MS: (M+H m/z=436.3).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Na+].[Na+].[Na+]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[P:14]([O-:18])([O-:17])([O-:16])=[O:15]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
165 ml of 0.1 M citric acid and 91 ml of 0.2 M dibasic sodium phosphate solution (Example 7) were mixed together to produce pH 3.8 citrate-phosphate (Mcllvaine) buffer and purged with nitrogen for two minutes.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:13][CH2:14][N:17]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(N2CCN(Cc3ccccc3)CC2)C1

Procedure:
4.90 g (21.1 mmol) of benzylbis(2-chloroethyl)amine hydrochloride were dissolved in ethanol (120 ml) and, while stirring, 5.00 g (21.1 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate hydrochloride and 14.2 g (169 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added, and the aqueous phase was extracted with ethyl acetate (4×60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% methanol in dichloromethane). Yield: 6.99 g (75%) of yellow solid
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].C(Cl)(=O)C(Cl)=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CCN(CC)CC>C1COCC1.CN(C=O)C>[C:1]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:7])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C1CCNC1
Reactant: C#CCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of 4-pentynoic acid (981 mg, 10 mmol) in THF (40 mL) and DMF (2 drops) was added dropwise oxalyl chloride (0.96 mL, 11 mmol) over 10 min. The solution was stirred for 3 h at rt, then the flask was cooled in an ice bath and a solution of pyrrolidine (1.65 mL, 20 mmol) and Et3N (1.74 mL, 12.5 mmol) in THF (10 mL) was added dropwise over 17 min. The resulting suspension was stirred overnight, then filtered. The filtrate was partitioned between EtOAc (300 mL) and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to dryness, giving the desired product as a brown solid (1.32 g, 87%). MS (APCI(+)) m/e 152.1 (M+H)+.