Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:7])[C:4](Cl)=[O:5])[CH3:2].[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2=[O:18])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:18]=[C:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH3:7])[CH:17]=2)[CH2:13][CH2:14]1
Reactant: CCN(C)C(=O)Cl
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C)C(=O)Oc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Ethylmethyl carbamyl chloride (15.5 g, 127.57 mmol) was added to a stirred suspension of 6-hydroxy-1-indanone (17.2 g, 116.1 mmol) and potassium carbonate (31.8 g, 188 mmol) in acetonitrile (800 mL) at room temperature over a period of 15 minutes. The reaction mixture was heated to reflux and refluxed for 18 hours. The reaction mixture was cooled to ambient temperature, the solvent evaporated and the residue was diluted with water (250 mL) and extracted three times with toluene (250 mL). The combined organic phase was dried on MgSO4 and toluene was evaporated in a rotary evaporator. The crude crystalline product was purified by crystallization from 2-propanol (200 mL), collected by filtration, and dried under vacuum at 50° C. to afford the title compound (22 g, 81.5%). 1H NMR (300 MHz, CDCl3) δ ppm 7.47-7.44 (2H, m, Ar), 7.36 (1H, dd, J 8.4 and 2.1, Ar), 3.52-3.37 (2H, m, NCH2CH3), 3.14-3.108 [2H, m, OCCH2CH2 and incl. NCH3 (two rotamers), at 3.08 and 2.99 (3H, s, Me)], 2.74-2.71 (2H, m, OCCH2 CH2) and 1.25 and 1.19 (two rotamers) (3H, two triplets, J6.9). Mass Spectrum (FAB+) [MH+]=234
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([NH:8][C:9]1[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][N:10]=1)(=[O:7])[CH3:6]>C(Cl)Cl>[C:5]([NH:8][C:9]1[N:14]=[C:13]([CH2:15][Cl:3])[CH:12]=[CH:11][N:10]=1)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Nc1nccc(CO)n1
Solvent: ClCCl
Product: CC(=O)Nc1nccc(CCl)n1
Yield: 18 %

Procedure:
Thionyl chloride (0.18 mL, 2.4 mmol) was added to a suspension of 2-acetylamino-4-hydroxymethylpyrimidine (290 mg, 1.7 mmol, Reference Compound No. 4-3) in anhydrous methylene chloride (10 mL) at room temperature, and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure, then water (50 mL) and ethyl acetate (100 mL) were added thereto and the mixture was separated into the organic layer and the aqueous layer, and the aqueous layer was extracted twice with ethyl acetate (50 mL). The whole organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 68 mg of the title Reference Compound as a yellow solid (Yield: 18%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=1[O:38][CH3:39]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(CC(C)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CC(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2 mmoles), K2CO3 (3 ), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6 g, 18.2 mmoles) in acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). The dichloromethane was filtered and concentrated again. The crude material (6.4 ) was purified by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 700 ml; 1% methanol in dichloromethane, 1.4 l). The material thus purified (weight: 2.87 g, 51%) was recrystallized from ethanol (25 ml) to give 2.13 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]propanone as beige colored crystals, m.p.=118°-119° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:24]([OH:26])=[O:25])[C:15]([CH2:18][C:19]4[S:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N+]=[N-])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.C(OCC)(=O)C>[C:29]1([CH:35]([O:25][C:24]([CH:14]2[N:13]3[C:27](=[O:28])[C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C@H:12]3[S:17][CH:16]=[C:15]2[CH2:18][C:19]2[S:23][CH:22]=[CH:21][CH:20]=2)=[O:26])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(Cc3cccs3)=CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7β-phenylacetylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid in 150 ml of methanol is diluted with 200 ml of ethyl acetate, then treated with 9.70 g of diphenyldiazomethane in 20 ml of ethyl acetate. The reaction mixture is stirred at room temperature for 1 hour and evaporated to dryness under reduced pressure. The residue is crystallised from ethyl acetate and chromatographed on 400 g of silica gel. Elution with ethyl acetate yields the 7β-phenylacetylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid diphenylmethylester, which after recrystallisation from ethyl acetate melts at 166°-167°; [α]D20 = + 359° ± 2° (c = 0.490 in 95% ethanol); thin-layer chromatogram (silica gel): Rf = 0.73 (system: toluene/ethyl acetate 1:1) and Rf = 0.56 (system: toluene/acetone 4:1); ultraviolet absorption spectrum (in 95% alkanol): strong terminal absorption; infrared absorption spectrum (in mineral oil); characteristic bands at 2,97μ, 5,62μ, 5,75μ, 6,03μ and 6,54μ.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:12][S:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][C:23]=1[NH2:32])(=[O:15])=[O:14].Cl.N1C=CC=CC=1>C(#N)C>[CH2:2]([C:1]1[N:21]([CH2:20][CH2:19][O:18][CH2:17][CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:32]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(OC)(OC)OC
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
Trimethyl orthovalerate (1.3 g, 8.1 mmol) was added to a solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (˜2.3 g, ˜7.4 mmol) in acetonitrile (37 mL). Pyridine hydrochloride (˜100 mg) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 15 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was cooled and then concentrated under reduced pressure to provide ˜2.8 g of 2-butyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as a greenish-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH:9]C(OC(C)(C)C)=O)=[C:6]([F:17])[C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[I:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=[O:35])=O)=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])=[C:6]([F:17])[C:7]=1[N:8]1[C:34](=[O:35])[NH:33][C:31]([C:30]2[CH:36]=[CH:37][C:27]([I:26])=[CH:28][CH:29]=2)=[N:9]1
Reactant: O=C=NC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1F
Yield: 42.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate (Intermediate-57, 0.250 g), 4-iodobenzoyl isocyanate (Intermediate-67, 0.250 g), DCM (10 mL) and trifluoro acetic acid (0.5 mL) to afford 0.150 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.19 (s, 9H), 4.30 (d, J=3.3 Hz, 2H), 7.39 (m, 1H), 7.45 (d, 1H), 7.62 (d, 2H), 7.90 (d, J=3.6 Hz, 2H), 8.19 (t, 1H), 13.0 (br s, 1H); MS (m/z): 528.98 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:22])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[O:31]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18]1)[C@@H:3]([C:2](=[O:22])[CH3:1])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5α-pregnan-2-ene-20-one (3.05 g) in 50 mL of chloroform was treated with m-chloroperbenzoic acid (50-60%, 4.0 g). The solution was stirred at room temperature overnight (14 h) under an argon atmosphere. The solution was diluted with more chloroform (250 mL), washed with dilute potassium bicarbonate solution (2×150 mL), with water (2×100 mL), and finally with brine, and dried over magnesium sulfate and evaporated to an oil which crystallized on standing. Flash chromatography on a silica gel bed (200 g) and eluting with hexane/ethyl acetate (90:10) recovered in fraction 67-110 (collecting 20 mL volumes) 1.194 g of the title compound.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:13]([NH:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[N:12]=2)[CH2:6][CH2:5]1.O1CCCC1.[N:39]([Sn](CCCC)(CCCC)CCCC)=[N+:40]=[N-:41]>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[NH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[C:13]([NH:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]4[NH:41][N:40]=[N:39][N:31]=4)=[CH:28][CH:27]=3)[N:12]=2)[CH2:8][CH2:9]1
Reactant: N#Cc1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(-c4nnn[nH]4)cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 120 °C

Procedure:
296 mg of the product obtained in Example 83 in 3 ml of toluene and 0.26 ml of azido tributyltin are mixed together at ambient temperature then the reaction medium is heated at a temperature of approximately 120° C. for 22 hours then left to return to ambient temperature. 7 ml of tetrahydrofuran is added to the suspension obtained, gaseous hydrochloric acid is bubbled through for 1 minute then nitrogen is bubbled through for 10 minutes, the product obtained is separated, followed by rinsing with ether and drying under reduced pressure at 50° C. In this way 374 mg of expected product is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](NN)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[Br:20]Br>CCCCCC>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([Br:20])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: NNS(=O)(=O)c1cccc2cccnc12
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Br)c1cccc2cccnc12
Yield: 749.2 %

Procedure:
A 500 ml, single-neck flask equipped with a magnetic stirrer is charged with 6.59 g (0.0295 mol) of 8-quinolinesulfonyl hydrazine and 200 ml of chloroform. Crushed ice is added, and the slurry is vigorously stirred. 9.50 g of bromine is added dropwise to the slurry with stirring. After the addition of bromine is complete and all of the bromine color has disappeared, the layers are separated. The chloroform layer is dried over anhydrous magnesium sulfate, and the chloroform is removed in vacuo leaving a pale yellow solid. The solid is slurried with hexane, filtered, and vacuum dried to give 6.00 g (0.221 mol) of 8-quinolinesulfonyl bromide m.p. 142°-144° C.
Reaction SMILES: [CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:5]2C(=O)OC(C)(C)[O:7][C:6]2=[O:14])[CH2:3][CH2:2]1>CN(C=O)C.O.O>[CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:5][C:6]([OH:14])=[O:7])[CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C(C(c2cccc(O)c2)C2CC2)C(=O)O1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CC(c1cccc(O)c1)C1CC1
Yield: 100 %

Procedure:
5-(Cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 66.6T (14.64 g, 50.43 mmol) in DMF/water (10/1) (220 mL) was heated at 90° C. overnight. The reaction was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 66.6U as a clear oil (10.40 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:21].[BrH:29].[OH-].[Na+]>CS(C)=O>[Br:29][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[CH:4][C:3]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:21])=[C:2]([Cl:1])[CH:7]=2)=[C:10]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH:11]=1
Reactant: Br
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2COCCO)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Compound 156 (3.8 g, 9.6 mmol) was dissolved in DMSO (115 mL). The solution was cooled on an ice bath and 48% aqueous HBr (32 mL, 285 mmol) was added slowly. The solution was stirred in a closed vessel at room temperature for 5 days. The reaction mixture was cooled on an ice bath and 27% aqueous NaOH (30 mL) was added to give a basic solution. The water phase was extracted three times with EtOAc, the combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:1 as the eluent to afford the title compound as a slightly coloured crystalline compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=O)N[C:9]2[CH:13]=[CH:14][CH:15]=C[C:8]=2[O:7]1)=[O:5])[CH3:2].[H-].[Na+].IC.C(OCC)(=O)C.[CH3:27][N:28]([CH3:31])[CH:29]=[O:30]>>[CH3:11][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:15]=[CH:14][CH:13]=[CH:9][C:8]=2[O:7]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1Oc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)C1(C)Oc2ccccc2N(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.5 mmol (1.2 g) of 2-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazin-3-one (described in C.R. Acad. Sci. Paris Series C, 1969, 269, 154) in 5 ml of dimethylformamide are added at 0° C. to a suspension of 11 mmol (0.44 g) of 60% sodium hydride in 5 ml of dimethyformamide. The reaction mixture is stirred at 0° C. for 30 minutes. 22.2 mmol (1.38 ml) of iodomethane are then added, and the reaction mixture is stirred at room temperature for 1 hour. After hydrolysis and extraction with ethyl acetate, the organic phase is dried, concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (3/7) as eluant to yield the expected compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.Cl>C1COCC1>[Br:9][C:10]1[S:11][C:12]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Brc1cccs1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2ccc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
To a -78° C. solution of LDA (19.3 mmol) in THF was added 2-bromothiophene (3.00 g, 18.4 mmol) and the reaction mixture was stirred for 15 min. A solution of 4-fluorobenzyl bromide (3.65 g, 19.3 mmol) in THF (1 mL) was added dropwise and the reaction mixture was warmed slowly to ambient temperature and stirred for 70 hours. The reaction mixture was poured into 0.5N aqueous HCl and extracted twice with ether. The combined organic layers were washed with saturated aqueous NaHCO3 (2×) and brine, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (hexanes, then 3% ether/hexanes) gave 2-bromo-5-(4-fluorophenylmethyl)thiophene (2.25 g, 45%).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1>C(O)C>[CH2:2]([O:1][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)[CH3:3]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Add sodium ethoxide (1.6 mL of 21% w/v in ethanol, 4.8 mmol) to a solution of 6-chloronicotinonitrile (612 mg, 4.41 mmol) in anhydrous ethanol (15 mL) and heat the reaction at reflux for 3 h. Cool to room temperature and stir overnight under nitrogen atmosphere. Concentrate in vacuo and dissolve the residue into dichloromethane. Wash with saturated aqueous NaHCO3, dry over MgSO4 and concentrate in vacuo to give the desired intermediate as an off-white solid (545 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:19])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[OH-].[Na+]>C1COCC1>[OH:19][C:9]1([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: COc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCC(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the ketal of step D (11.5 g, 43.3 mmol) in THF (100 mL) was added 3N HCl (75 mL) and the solution stirred overnight at rt. The pH of the solution was adjusted to ˜11 by the addition of 3N NaOH solution. After removal of most of the THF by rotary evaporation, the aqueous was extracted with CH2Cl2 (3×). The combined extracts were dried (MgSO4), filtered, and concentrated to give the title compoun as a yellow solid; yield 8.2 g, 37.1 mmol, 86%; 1H NMR (CDCl3) δ 8.26 (s, 1H), 7.75 (d, 1H), 6.73 (d, 1H), 3.91 (s, 31), 2.91 (m, 2H), 2.78 (s, 1H), 2.32 (m, 2H), 2.21(m, 4H); MS m/z=222.1.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26]Br.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(#N)C.C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:23][O:24][CH2:25][CH2:26][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: COCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.75 g, 17 mmol), K2CO3 (3 g, 21.7 mmol), bromoethyl methyl ether (2.84 g, 20.4 mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. The reaction was cooled. The inorganics were filtered and rinsed with DCM. The organic solution was concentrated down to an oil (7 g). Purification on a flash chromatography column (SiO2, 45 g; eluted with methanol/DCM) gave a light yellow oil as product (4 g, 87%). This oil was dissolved into ethanol and treated with a solution of fumaric acid (1.67 g) in ethanol (20 ml). White crystals (5.15 g) were collected, m.p.=157°-158° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.C(N(CC)CC)C>[Ni].C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(Br)cc1N
Yield: 104.7 %

Procedure:
A solution of 4-bromo-2-nitro-anisole (7.7 g, 33.1 mmol), triethylamine (4.6 ml, 33.1 mmol) and Raney Nickel catalyst (4 g) was vigorously stirred in ethanol (300 ml) under an atmosphere of hydrogen for 1 h at 20° C. After this time the theoretical amount of hydrogen had been absorbed (2.5 l), so the catalyst was filtered off and the solvent evaporated to afford the title compound as a light yellow solid (7 g, 104% yield), MS: m/e=201 (M+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([F:19])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:20][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Oc1cc(F)cc(F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cc(F)cc(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 3,5-difluorophenol.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:9][C@H:8]([CH3:10])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To D-alanine tert-butyl ester hydrochloride (1 g) in methylene chloride (35 ml) solution, triethylamine (1.7 ml) and 4-chlorobenzenesulfonyl chloride (1.1 g) were added under ice cooling and the mixture was stirred at room temperature for 2 hours. The methylene chloride was distilled off in vacuo, then the residue was diluted with ethyl acetate. The obtained solution was successively washed with distilled water, saturated potassium hydrogensulfate aqueous solution, and saturated saline, dried over with anhydrous sodium sulfate, then concentrated. The residue was recrystallized from ethyl acetate/hexane to obtain the title compound (1.47 g).
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][O:8][B:7]([OH:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[C:58]([NH:62][NH2:63])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C>[C:58]([NH:62][NH:63][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[B:7]([OH:11])[O:8][CH2:9][C:10]=2[C:2]=1[F:1])=[O:14])([CH3:61])([CH3:60])[CH3:59]
Reactant: O=C(O)c1ccc2c(c1F)COB2O
Reactant: CC(C)(C)NN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NNC(=O)c1ccc2c(c1F)COB2O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Following the general procedure, mixed together 4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxylic acid (0.500 g, 2.55 mmol), PyBOP (1.34 g, 2.55 mmol), DIEA (0.89 mL, 5.10 mmol) in DMF (6 mL) followed by the addition of tert-butyl hydrazine hydrochloride (0.318 g, 2.55 mmol) and stirred the mixture at 40° C. for 1 h. LCMS showed a main peak at 2.43 with the expected product mass of 267.01 (M+1). After the general work up procedure, the crude dry sample (SKC-07-069, 0.800 g, contains some DMF) was used for the next step without further purification.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH2:11]>>[C:1]([O:6][CH2:7][CH:8]([CH2:9][OH:11])[OH:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: O
Product: C=C(C)C(=O)OCC(O)CO

Procedure:
Glycidyl methacrylate is immiscible with water, but as the reaction proceeds, solubility is increased until a clear solution is obtained. As the reaction proceeds, glyceryl methacrylate is formed which co-dissolves the unreacted glycidyl methacrylate.