Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:12][CH:11]2[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][NH:9][CH2:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[NH2-].[Li+].[CH3:18][C:19]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:20]=1[CH2:21]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:1]([N:5]1[CH2:6][CH:7]2[C:13]([CH3:14])([CH3:15])[CH:11]([CH2:10][N:9]([CH2:21][C:20]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:19]=3[CH3:18])[CH2:8]2)[CH2:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC2CNCC(C1)C2(C)C
Reactant: Cc1ccc(C)c(CCl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [NH2-]
Solvent: CN(C)C=O
Product: CCCCN1CC2CN(Cc3cc(C)ccc3C)CC(C1)C2(C)C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
3.5 g 3-n-butyl-9,9-dimethyl-3, 7-diazabicyclo[3,3,1]nonane were dissolved in 25 ml of dimethyl formamide, and 0.8 g of lithium amide was added to the solution. The reaction mixture was then maintained at a temperature of 60° C. for 1 hour and subsequently allowed to cool. After cooling, a solution of 5.6 g of 2,5-dimethylbenzyl chloride in 10 ml of dimethyl formamide was added dropwise, and the reaction mixture was stirred for a further 4 hours at 80° C. Then aqueous citric acid solution was added to the reaction mixture in order to dissolve the title compound as a citric acid salt. The solution was washed with diethyl ether and then rendered alkaline by adding dilute sodium hydroxide solution, whereupon the title compound was again freed as a base. The free base was extracted with diethyl ether. After the ether extract was dried over magnesium sulfate, the ether solution was filtered, and the ether was distilled off. The remaining oil was purified by distillation in a bulb tube at 210° C. and 0.01 Torr.
Reaction SMILES: [C:1]([O:8][C@@H:9]1[C@@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([CH3:26])[O:20][C@@H:10]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C([Sn](=O)CCCC)CCC.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:37]([O:24][C@H:23]1[C@@H:22]([OH:25])[C@@H:21]([CH3:26])[O:20][C@H:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C@@H:9]1[O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(O[C@H]2O[C@H](C)[C@H](O)[C@H](O)[C@H]2OC(=O)CCC(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[Sn](=O)CCCC
Agent: [I-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(O[C@H]2O[C@H](C)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OC(=O)CCC(C)=O)cc1
Temperature: 60 °C

Procedure:
4-Methoxyphenyl 2-O-levulinoyl-α-D-fucopyranoside (2.37 g, 6.46 mmol) and dibutyl tin oxide (1.61 g, 6.46 mmol) are dissolved in 70 mL of toluene. The mixture was refluxed with a Dean-Stark trap for 2.5 h. Then it was cooled to 60° C., benzylbromide and tetrabutylammonium iodide were added and refluxed for 2 h. After cooling to room temperature the reaction mixture was diluted with water and extracted 3 times with EtOAc, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (3:2 hexane/EtOAc) yielding 2.82 g (95%, 2 steps) of 6 as a colorless oil: [α]D: +140.8 (c=0.35, CHCl3). IR (thin film, CHCl3): 3015, 1739, 1713, 1503, 1362, 1050 cm−1. 1H NMR (CDCl3, 300 MHz) δ 1.29 (d, J=6.6 Hz, 3H), 2.14 (s, 3H), 2.62 (m, 3H), 2.72 (m, 2H), 3.76 (s, 3H), 3.92 (s, 1H), 4.09 (m, 2H), 4.74 (s, 2H), 5.28 (dd, J=10.2 Hz J=3.9 Hz, 1H), 5.50 (m, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 7.33 (m, 5H). 13C NMR (CDCl3, 75 MHz) 16.2, 28.1, 29.9, 37.9, 55.7, 66.2, 69.8, 70.0, 72.4, 75.6, 96.2, 114.5, 118.0, 118.2, 127.6, 127.7, 127.9, 128.5, 137.7, 150.7, 155.0, 172.0, 206.0. MALDI-HRMS: m/z [M+Na]+ calcd 481.1833, obsd 481.1824.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1.Cl.[CH3:44][O:45][CH:46]1[CH2:49][NH:48][CH2:47]1.CN(C=O)C>CCOC(C)=O>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=[C:2]([N:48]2[CH2:49][CH:46]([O:45][CH3:44])[CH2:47]2)[C:11]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: COC1CNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1CN(c2nc3ccc(C(O)(c4ccc(C(F)(F)F)nc4)c4cncn4C)cc3c(Cl)c2Cc2ccc(-n3cccn3)cc2)C1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (200 mg, 0.328 mmol, Intermediate 65), 3-methoxyazetidine hydrochloride (427 mg, 3.28 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The reaction vessel was then cooled to room temperature and the contents were transferred to a separatory funnel with EtOAc dilution, and extracted once with saturated, aqueous NH4Cl solution, then extracted three times with deionized water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C34H29ClF3N7O2, 659.2. m/z found, 660.3 [M+H]+. 1H NMR (600 MHz, CD3OD) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.11 (dd, J=2.5, 0.4 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.2, 2.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.77-7.73 (m, 2H), 7.67 (d, J=1.4 Hz, 1H), 7.62-7.59 (m, 2H), 7.59-7.56 (m, 1H), 7.17 (d, J=8.7 Hz, 2H), 6.49-6.46 (m, 1H), 6.37 (s, 1H), 4.34-4.29 (m, 4H), 4.19-4.13 (m, 1H), 4.02-3.97 (m, 2H), 3.48 (s, 3H), 3.22 (s, 3H).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[Cl:13][CH2:14][CH2:15][CH2:16]Br>CN(C)C=O>[Cl:13][CH2:14][CH2:15][CH2:16][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3][C:4]1=[O:12]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc2ccccc2n1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a stirred suspension of sodium hydride (7.8 g, 160 mmol, ether-washed) in dimethylformamide (75 ml) was added dropwise under nitrogen, 2-benzoxazolinone (20.0 g, 150 mmol) dissolved in dimethylformamide (150 ml). After complete addition the reaction was stirred at ambient temperature for 30 min, and then it was cooled to -5° C. with an ice-acetone bath. A solution of 3-chloro-1-bromopropane (46.6 g, 300 mmol) in dimethylformamide (50 ml) was added dropwise (temperature never exceeded 0° C.). The reaction was allowed to reach ambient temperature and was stirred for 16 hours. The reaction was poured into waiter, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the extract concentrated to afford 21.9 g of a brown solid. The solid was recrystallized from toluene-hexane to afford N-(3-4chloropropyl)-2-benzoxazolinone as large needles, 15.6 g, m.p.=264°-266° C.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[Cl-].[CH2:25]([Zn+])[CH3:26].Cl[SiH]1CCC(CC[C@H]2CC[C@H](C3C=CC(F)=CC=3)CC2)CC1.[Cl-].C([Zn+])CCCC>>[F:23][C:18]1[CH:17]=[C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:25][CH3:26])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC[Zn+]
Reactant: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1F
Agent: CCCCC[Zn+]
Agent: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1
Agent: [Cl-]
Product: CC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 6, except that 7.5 g (21 mmol) of 1-chloro-4-(2-(trans-4-(3,4-difluorophenyl)cyclohexyl)ethyl)-1-silacyclohexane and ethylzinc chloride were used instead of 7.0 g (21 mmol) of 1-chloro-4-(2-(trans-4-(p-fluorophenyl)cyclohexyl)ethyl)-1-silacyclohexane and n-pentylzinc chloride.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C

Procedure:
2,6-Dichloro-9H-purine (20 g, 0.11 mol) and 4-toluenesulphonic acid monohydrate (0.2 g) were dissolved in ethyl acetate (300 ml), the mixture was heated to 50° C. and a solution of 3,4-dihydro-2H-pyran (12.6 ml, 0.14 mol) in ethyl acetate (50 ml) was added slowly over 30 minutes. The reaction mixture was cooled to room temperature, water (100 ml) was added and the pH of the solution was adjusted to 7 by addition of a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was azeotroped with pentane (100 ml) to afford the title compound as a slightly impure white solid (30.9 g).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[Cl:1][C:2]1[N:3]([C:15]2[CH:16]=[CH:17][S:13][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: OB(O)c1ccsc1
Product: O=Cc1c(Cl)n(-c2ccsc2)c2ccccc12

Procedure:
The title compound was prepared analogously as described in example 9, step 2, using 2-chloro-1H-indole-3-carbaldehyde (300 mg, 1.67 mmol) and thiophene-3-boronic acid. Yield: 123 mg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[N+:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:3][CH:4]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(N2CCNCC2)c2ccccc12
Temperature: 60 °C

Procedure:
Treat a slurry of 1-chloro-4-nitro-isoquinoline (2.5 g, 12 mmol) in acetonitrile (100 mL) with solid piperazine (5.2 g, 60 mmol). Heat the resulting yellow mixture overnight at 60° C. After cooling to ambient temperature, partition the reaction mixture between ethyl acetate and a saturated aqueous sodium bicarbonate solution. Add MeOH, dichloromethane and ethyl acetate, and filter the entire mixture to give a bright yellow solid. (2.15 g, 69%; LCMS ES+ (m/z) 259 [M+H]).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=O.[CH3:16][C:17]1(C)[O:22]C(=O)[CH2:20][C:19](=O)[O:18]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.ClCCl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13](=[O:15])[CH2:16][C:17]([O:18][CH2:19][CH3:20])=[O:22]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a solution of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (3.01 g, 14.67 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.23 g, 15.47 mmol) and 4-dimethylaminopyridine (2.73 g, 22.35 mmol) in dichloromethane (150 mL) was added a solution of DCC (3.36 g, 16.28 mmol) in DCM (50 mL) at 0° C. The mixture was stirred at RT for 16 h. The insoluble materials were filtered off, and the filtrate was washed with 5% NaHSO4 aqueous solution. The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was treated with EtOH (200 mL) and the resulting mixture was stirred at 70° C. for 4 h and then concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with EtOAc. The organic layers were washed with water and brine, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with IPE to give the title compound as a colorless solid (3.43 g, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (t, J=6.8 Hz, 3H), 3.58 (s, 2H), 4.24 (q, J=6.8 Hz, 2H), 4.67 (s, 2H), 7.73-7.78 (m, 2H), 7.86-7.91 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5](OCCC)=[N:6][NH:7][C:8]([O:10]C)=O)[CH2:2][CH3:3].[CH3:16][NH2:17]>CO.C(O)C>[CH2:1]([O:4][C:5]1[N:17]([CH3:16])[C:8](=[O:10])[NH:7][N:6]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=NNC(=O)OC)OCCC
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CCCOc1n[nH]c(=O)n1C
Temperature: 100 °C

Procedure:
693.6 g (94.4%) of methyl N′-dipropoxymethylenehydrazinecarboxylate (3 mol) were dissolved in 1752 g of methanol and admixed with 564.7 g (6 mol) of methylamine, dissolved in ethanol, and the mixture was heated in an autoclave at 100° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, the residue was taken up in water (880 ml) the mixture was extracted with methylene chloride and the extract was concentrated under reduced pressure. The crystals which precipitated out on cooling were filtered off and dried. This gave 383 g (71.2%, content 87.6%) of 5-propoxy-4-methyl-2,4-dihydro-1,2,4-triazol-3-one in the form of a solid. Melting point: 72.5-73.5° C.
Reaction SMILES: [CH2:1]([C:4]1([C:28]([O:30]C)=[O:29])[NH:9][C:8](=[O:10])[C:7]2[S:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:6]=2[CH:5]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH:2]=[CH2:3].[OH-].[Na+].O>CO.O1CCCC1>[CH2:1]([C:4]1([C:28]([OH:30])=[O:29])[NH:9][C:8](=[O:10])[C:7]2[S:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:6]=2[CH:5]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)OC)NC(=O)c2sc(N3CCOCC3)cc2C1c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCC1(C(=O)O)NC(=O)c2sc(N3CCOCC3)cc2C1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.8 %

Procedure:
A mixture of methyl 5-allyl-4-(3,4-dichlorophenyl)-2-(morpholin-4-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (0.118 g, 0.245 mmol), methanol (2.0 mL), tetrahydrofuran (2.0 mL) and a solution of 1.0 M sodium hydroxide in water (1.50 mL, 1.50 mmol) was stirred at rt overnight. Additional methanol (2.0 mL) and 1.0 M Sodium hydroxide in water (1.50 mL, 1.50 mmol) was added. The mixture was stirred at rt for 2 days. The mixture was concentrated to remove most of volatile solvents and then acidified by 1M HCl. The precipitate was collected and dried in air to afford crude product. Final purification by HPLC afforded pure product as a white solid (43.3 mg, 23%). LCMS (FA) ES+: 467, 469. 1H NMR (400 MHz, DMSO) δ 7.45 (d, J=8.3 Hz, 1H), 7.38 (s, 1H), 7.25 (br s, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.50 (s, 1H), 6.04 (s, 1H), 5.74-5.63 (m, 1H), 4.99-4.89 (m, 2H), 4.18 (s, 1H), 3.68 (br s, 4H), 3.12 (br s, 4H), 2.54-2.50 (m, 2H, overlapping with DMSO peak).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]([CH3:20])=[O:19]>[N+](C)([O-])=O>[OH:19][C:18]([C:7]1([O:6][CH3:5])[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)([CH3:20])[C:17]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)C(C)(O)C1(OC)C=Cc2ccccc2C1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (162 g, 12,2 mmol) was added in 3 portions to a solution of 2-methoxynaphthalene (1,28 g, 8,09 mmol) in nitromethane (20 mL) at 5° C. Ethyl pyruvate (1,41 g, 12,2 mmol) in nitromethane (10 mL) was added over 1 hour at this temperature. The reaction was allowed to proceed for 1 hour and warmed to 20° C. for 2 hours. Ethyl 2-hydroxy-2-(6-methoxynaphth-6-yl)propionate was formed with a selectivity of 16% at 52% conversion of the starting material.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]([CH3:32])([CH3:31])[CH2:5][C:6]1[N:7]=[C:8]([C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:9]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:10]=1>O1CCCC1>[CH3:3][C:4]([CH3:32])([CH3:31])[CH2:5][C:6]1[N:7]=[C:8]([C:17]([OH:30])([CH3:1])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:9]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:12])=[O:13])[CH:10]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-n2cccn2)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Methyllithium (1.6 M in diethyl ether) (0.327 mL, 0.524 mmol) was added to a −78° C. solution of 4-(2,2-dimethylpropyl)-N,N-dimethyl-2-{[4-(1H-pyrazol-1-yl)phenyl]acetyl}-1H-imidazole-1-sulfonamide (75 mg, 0.175 mmol) in tetrahydrofuran (2 mL). After stirring at −78° C. for 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% EtOAc/hexane afforded 4-(2,2-dimethylpropyl)-2-{1-hydroxy-1-methyl-2-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@:17]([CH3:23])([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C@@:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:23])[CH:20]([CH3:22])[CH3:21]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CC(C)[C@@](C)(N)CO
Product: CC(C)[C@](C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2R)-2-amino-2,3-dimethyl-1-butanol (CAN 155158-75-1) as starting materials and isolated (19 mg, 19%) as colorless oil; LC-MS (UV peak area, m/z) 98.6%, 327.1464 (MH+).
Reaction SMILES: [C:1]([O:5][P:6]([O-:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)C.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1>C1COCC1>[OH:30][CH:29]([P:6](=[O:12])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:26]1[CH:27]=[CH:28][C:23]([CH3:31])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OP([O-])OC(C)(C)C
Reactant: Cc1ccc(C=O)cc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of di-tert-butylphosphite (30 g) in THF (700 mL) cooled at −78° C. was added dropwise a solution of LiN(TMS)2 (165 mL, 1M in THF). After stirring for 30 min at −78° C., a solution of 4-tolualdehyde (18 mL in 100 mL of THF) was added. The reaction mixture was stirred for 30 min at −78° C. and 2 h at 0° C., and then quenched with 400 mL of 50% saturated aqueous NH4Cl solution. The mixture was extracted with 1 L of 2:1 hexane/EtOAc and the extract was dried over Na2SO4. After concentration and swishing from hexane, 32 g of the title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[C:6]([I:15])[C:5]2=[O:16].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[C:6]([I:15])=[C:5]2[O:16][CH2:23][CH3:24]
Reactant: CCI
Reactant: COc1cc2[nH]c(C)c(I)c(=O)c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(I)c(C)nc2cc(OC)c(Cl)cc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of 6-chloro-3-iodo-7-methoxy-2-methylquinolin-4(1H)-one (2.00 g, 5.72 mmol) in dimethylformamide (57 ml) was added potassium carbonate (1.58 g, 11.4 mmol) at room temperature. The resulting suspension was stirred 0.5 hours at 50° C. Ethyl iodide was added dropwise at room temperature, and the reaction mixture was stirred 8 hours at 50° C. The solvent was removed in vacuo and the resulting residue was resuspended in ethyl acetate and water. The organic layer was extracted with brine, dried over magnesium sulfate and concentrated in vacuo to give 2.12 g (99% yield) of 6-chloro-4-ethoxy-3-iodo-7-methoxy-2-methylquinoline as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.40 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 4.02 (s, 3H), 2.92 (s, 3H), 1.61 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH3:9])[C:4](=O)[N:5]([CH3:7])[CH3:6])[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:3]([CH3:9])[C:4]([N:5]([CH3:7])[CH3:6])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH3:2]
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CCN(C)C(=O)N(C)C
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-ethyl-1,1,3-trimethylurea (6.57 g) in benzene (70 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) for 45 hours at 65°-70° C. gave 1-ethyl-2-(2-morpholinophenyl)-1,3,3-trimethylguanidine (bp. 140° C. at 0.2 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH2:18][C:19]#[N:20])[C:5]([NH:7][C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:14][C:13]3[C:8]([N:7]=2)=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][C:19]#[N:20]
Reactant: N#CCc1ccc(C(=O)Nc2ncccc2O)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCc1ccc(-c2nc3ncccc3o2)cc1Cl
Temperature: 25 °C

Procedure:
3-chloro-4-(cyanomethyl)-N-(3-hydroxypyridin-2-yl)benzamide (550 mg, 1.9 mmol) was refluxed in POCl3 (15 mL) for 2.5 h. Excess POCl3 was removed by distillation and the mixture was cooled to rt. The crude mixture was diluted with H2O. The aqueous layer was made basic (pH 14) with 1N NaOH and extracted with CH2Cl2 (3×20 mL). The residue was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexane gradient to afford (2-chloro-4-[1,3]oxazolo[4,5-b]pyridin-2-ylphenyl)acetonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.65–8.63 (d, 1H), 8.41 (s, 1H), 8.30–8.27 (d, 1H), 7.93–7.90 (d, 2H), 7.77–7.74 (d, 2H), 7.38–7.34 (m, 2H) 3.95 (s, 2H). MS (ESI) 270 (M+H)+.
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>C(O)C>[C:2]1([N:1]=[C:8]2[N:12]([CH3:22])[C:11]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][S:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C)c1csc(Nc2ccccc2)n1
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)C(C)c1csc(=Nc2ccccc2)n1C
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-(2-anilinothiazol-4-yl)-propionate (6.15 g), methyl iodide (17 ml) and ethanol (17 ml) is heated at 100° C for 11.5 hours in a sealed tube. The resultant mixture is treated with potassium carbonate in the same manner as in Example 1 (2) to give ethyl 2-(2-phenylimino-3-methyl-4-thiazolin-4-yl)propionate (1.6 g) melting at 80°-81° C (recrystallized from ether/hexane).