Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[C:49](/[CH:51]=[CH:52]/[C:53]([O:55][CH3:56])=[O:54])[CH:48]=[CH:47][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41](=[O:44])[O:42][CH3:43])=[CH:35][C:34]=2[O:45][CH3:46])[CH:22]=1)[CH2:18]O.[Br:57]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:50]=[C:49](/[CH:51]=[CH:52]/[C:53]([O:55][CH3:56])=[O:54])[CH:48]=[CH:47][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41](=[O:44])[O:42][CH3:43])=[CH:35][C:34]=2[O:45][CH3:46])[CH:22]=1)[CH2:18][Br:57]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)/C=C/c1ccc(OCCCCCCCCOc2cc(CO)cc(OCCCCCCCCOc3ccc(/C=C/C(=O)OC)cc3OC)c2)c(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(OCCCCCCCCOc2cc(CBr)cc(OCCCCCCCCOc3ccc(/C=C/C(=O)OC)cc3OC)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
2.39 g (3.08 mmol) of 3,5-bis[(8-{2-methoxy-4-[(1E)-3-methoxy-3-oxo-1-propenyl]phenoxy}octyl)oxy]benzyl alcohol, 1,14 g (3.42 mmol) tetrabromomethane were dissolved in 25 ml dichloromethane. The solution was subsequently cooled to 0° C. and a solution of 0.86 g (3.29 mmol) triphenylphosphine in 20 ml dichloromethane was added dropwise thereto over a period of 1 hour. The mixture was subsequently allowed to react for 20 h at 25° C. and reduced in volume by evaporation. Chromatography of the residue on 120 g silica gel using first toluene:ethyl acetate (19:1) then (4:1) as eluant yielded 1.94 g (78%) 3,5-bis[(8-{2-methoxy-4-[(1E)-3-methoxy-3-oxo-1-propenyl]phenoxy}octyl)oxy]benzyl bromide as colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:24])[NH:13][C:14]1[CH:15]=[N:16][C:17]([C:20](=[O:23])[CH2:21]Br)=[CH:18][CH:19]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[N:34]=2)[N:29]=[CH:28][C:27]=1[OH:38].ClCCl>CN(C)C=O.CO>[C:7]([O:11][C:12](=[O:24])[NH:13][C:14]1[CH:15]=[N:16][C:17]([C:20](=[O:23])[CH2:21][O:38][C:27]2[CH:28]=[N:29][C:30]3[C:35]([C:26]=2[NH2:25])=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[CH:18][CH:19]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc2ncc(O)c(N)c2n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2ncc(OCC(=O)c3ccc(NC(=O)OC(C)(C)C)cn3)c(N)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
Potassium carbonate (140 mg, 1.02 mmol, 1.5 eq) is added at room temperature to a stirred solution of [6-(2-bromo-acetyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (220 mg, 0.70 mmol, 1.0 eq) and 4-amino-6-methoxy-[1,5]naphthyridin-3-ol (130 mg, 0.69 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL). After 30 minutes stirring at room temperature, solvent is removed and the residue is extracted with ethyl acetate (3×15 mL) and water (10 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 100:1, v/v) to afford {6-[2-(4-amino-6-methoxy-[1,5]naphthyridin-3-yloxy)-acetyl]-pyridin-3-yl}-carbamic acid tert-butyl ester as a red-brown solid (90 mg, 24% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)/[C:10](O)=[O:11])=[CH:4][C:3]=1[O:23][CH3:24].P([N:41]=[N+:42]=[N-:43])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.CCN(CC)CC>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)/[C:10]([N:41]=[N+:42]=[N-:43])=[O:11])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cc(/C=C(/C(=O)O)c2ccc(OC(C)C)cc2)ccc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(/C=C(/C(=O)N=[N+]=[N-])c2ccc(OC(C)C)cc2)ccc1F
Reaction time: 16 h
Yield: 51.4 %

Procedure:
(E)-3-(4-fluoro-3-methoxyphenyl)-2-(4-isopropoxyphenyl)acrylic acid (4.38 g, 13.26 mmol), (PhO)2PON3 (2.71 mL, 12.60 mmol), and Et3N (3.70 mL, 26.5 mmol) were dissolved in benzene and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography using 20% EtOAc/Hexanes to give (E)-3-(4-fluoro-3-methoxyphenyl)-2-(4-isopropoxyphenyl)acryloyl azide (2.3 g, 49% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 (s, 1H), 7.16-7.11 (m, 2H), 6.97-6.92 (m, 2H), 6.84-6.78 (m, 1H), 6.63-6.53 (m, 2H), 4.63-4.54 (m, 1H), 3.49 (s, 3H), 1.38-1.35 (m, 6H).
Reaction SMILES: N1C2C[C@H:7]([CH2:10][OH:11])[CH2:6][C:5]=2[CH:4]=CC=1.C([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[N:14]1[C:15]2[CH2:16][CH2:4][CH2:5][C:6]=2[C:7]([CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:18][CH:17]=1
Reactant: CCN(CC)CC
Reactant: OC[C@@H]1Cc2cccnc2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCc1ccnc2c1CCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 102.7 %

Procedure:
To a solution of 895 mg (6 mmol) of (+)-(6R)-(6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol in 50 ml of anhydrous dichloromethane was added at −15° C. 0.918 ml (6.6 mmol) of triethylamine and 0.465 ml (6 mmol) of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 45 min. The mixture was then diluted with water and dichloromethane and extracted with dichloromethane. Organic layer was dried and evaporated to give 1.4 g (100%) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-4-ylmethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([C:19]1[CH:20]=[CH:21][C:22]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:26](=[O:35])[CH2:25][O:24][C:23]=2[N:36]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:49][CH3:50].[CH2:51]1COC[CH2:52]1>>[C:1]([O:5][C:6](=[O:37])[N:7]([C:19]1[CH:20]=[CH:21][C:22]2[N:27]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[C:26](=[O:35])[C:25]([CH2:49][CH3:50])([CH2:51][CH3:52])[O:24][C:23]=2[N:36]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)OCC(=O)N3c2ccc(Cl)cc2)c(OC)c1
Reactant: CCI
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCC1(CC)Oc2nc(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)ccc2N(c2ccc(Cl)cc2)C1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
[1-(4-Chloro-phenyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (370 mg, 0.66 mmol) was dissolved in THF (8 mL) and cooled to −78° C. LiHMDS (1 M solution in THF, 2 mL, 1.98 mmol) was added and the mixture stirred at −78° C. for 15 minutes. Iodoethane (160 mL, 1.98 mmol) was then added to the mixture, the cooling bath removed and then stirring continued for a further 15 minutes, during which time, the mixture reached ambient temperature. Saturated aqueous ammonium chloride and EtOAc were added. The EtOAc layer was isolated and washed with dilute aqueous potassium hydrogen phosphate solution. The EtOAc layer was then washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using SiO2 chromatography (10-30% EtOAc/Petrol) to give [1-(4-chloro-phenyl)-3,3-diethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (145 mg). MS: [M+H]+ 582.
Reaction SMILES: [NH2:1][OH:2].[C:3]1([C:9]2([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[O:14][CH2:13]C=[CH:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C>C(O)C>[OH:2][N:1]=[C:19]([C:18]1[CH:17]=[CH:16][C:15]([C:9]2([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:14][CH2:13][CH2:11][O:10]2)=[CH:22][CH:21]=1)[NH2:20]
Reactant: NO
Reactant: N#Cc1ccc(C2(c3ccccc3)OC=CCO2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(C2(c3ccccc3)OCCO2)cc1
Yield: 102 %

Procedure:
) Hydroxylamine (0.0449 mol) was added to a mixture of 4-(2-phenyl-1,3-dioxin-2-yl)benzonitrile (0.022 mol) in ethanol (88 ml). Then, N,N-diethylethanamine (0.0449 mol) was added dropwise and the resulting reaction mixture was stirred and refluxed for 3.5 hours. The solvent was evaporated. The residue was washed with water and this mixture was extracted with EtOAc. The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated, yielding 6.38 g of N′-hydroxy-4-(2-phenyl-1,3-dioxolan-2-yl)benzenecarboimidamide (interm. 10)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][S:21]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:22])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cccc(NS(=O)(=O)c2cccnc2)c1
Yield: 104.7 %

Procedure:
A solution of tert-butyl-3-aminobenzoate (100 mg, 0.5 mmol) and pyridine-3-sulfonylchloride (110 mg, 0.5 mmol) in pyridine (5 ml) was heated to 50° C. for 90 min. On cooling, the reaction was diluted with toluene (100 ml) and concentrated in vacuo. This was repeated with further aliquots of toluene until all the pyridine had been removed to afford the title compound as a yellow oil (175 mg). HPLC retention time 4.27 min. Mass spectrum (ES+) m/z 335 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=C[CH:5]=[C:6]2NC(=O)OC(=O)[C:7]=12.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].[C:22]([OH:25])(=O)[CH3:23]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:21][C:22](=[O:25])[C:23]=2[CH:3]=1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: CC(=O)O
Reactant: Nc1ccccc1N
Solvent: O
Product: O=C1Nc2ccccc2Nc2ccc(F)cc21
Temperature: 115 °C

Procedure:
6-Fluoro isatoic anhydride and 1,2-phenylenediamine were dissolved in acetic acid (80%) and the mixture heated at 115° C. for 2 hrs. The mixture was poured in water and extracted with ethyl acetate, washed with bicarbonate solution, dried and 2-fluoro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one was isolated (93%) by evaporation of solvent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (R)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methylsulfonyl)-phenylboronic acid following a procedure analogous to that described for Intermediate 6. Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[OH:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:1][C:28](=[O:29])[CH2:27][NH:26][C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C(=O)O)cc1O
Reaction time: 4 h

Procedure:
A solution of 9.75 g of 4-amino-3-hydroxybenzoic acid and 9.75 ml of triethylamine in 90 ml of dimethylformamide is heated to 80° C. 20 g of the N-hydroxysuccinimide ester of N-tert.-butoxycarbonylglycine are added and the reaction mixture is kept at 80° C. for 4 hours.
Reaction SMILES: [CH3:1][N:2]([C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[S:15])[CH:3]1[CH2:8][CH2:7][N:6](C(OCC)=O)[CH2:5][CH2:4]1.BrBr.C(Cl)(Cl)(Cl)[Cl:26]>>[ClH:26].[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[C:14]1[S:15][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: CCOC(=O)N1CCC(N(C)C(=S)Nc2ccccc2)CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: BrBr
Product: CN(c1nc2ccccc2s1)C1CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a suspension of ethyl 4-[methyl[(phenylamino)thioxomethyl]amino]-1-piperidinecarboxylate (4.02 g, 12.5 mmol) in carbon tetrachloride (25 mL) was added dropwise a solution of bromine (2.00 g, 12.5 mmol) in carbon tetrachloride (10 mL), the mixture was stirred at room temperature for 30 minutes, and heated to reflex for 1 hours. The insolubles were filtered, and washed with hexane. This was dissolved in 48% hydrobromic acid (40 mL), and the solution was heated to reflux for 2 hours. The reaction mixture was ice-cooled, neutralized with 25% aqueous ammonia, and extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. To the residue was added diisopropyl ether, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, a 10% hydrogen chloride-methanol solution (11 mL), and the mixture was concentrated under reduced pressure. The residue was recrystallized from methanol-diisopropyl ether to obtain 2.53 g of the title compound.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6]2[NH:8][C:9](=[O:12])[CH2:10][CH2:11][C:5]=2[C:4](=[O:13])[N:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=1.[C:26](=O)([O-])O.[Na+].IC.O>C(#N)C>[CH3:26][S:1][C:2]1[N:3]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:18][CH:19]=2)[C:4](=[O:13])[C:5]2[CH2:11][CH2:10][C:9](=[O:12])[NH:8][C:6]=2[N:7]=1
Reactant: O=C([O-])O
Reactant: O=C1CCc2c([nH]c(=S)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: CSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3,5,6-tetrahydropyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione (2.05 g) in acetonitrile (40 mL) were added 1M aqueous sodium hydrogen carbonate solution (5.52 mL) and iodomethane (1.73 mL), and the mixture was stirred at 50° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.1 g).
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:12]2[CH:11]=[CH:10][C:9]([Cl:14])=[CH:8][C:7]=2[S:4](=[O:6])(=[O:5])[N:3]=1.[OH-].[OH:16][CH2:17][CH2:18][N+:19]([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[CH3:1][C:2]1[N-:3][S:4](=[O:5])(=[O:6])[C:7]2[CH:8]=[C:9]([Cl:14])[CH:10]=[CH:11][C:12]=2[N:13]=1.[CH3:20][N+:19]([CH2:18][CH2:17][OH:16])([CH3:22])[CH3:21]
Reactant: CC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=Nc2ccc(Cl)cc2S(=O)(=O)[N-]1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A 12-L reaction flash was charged with 2.0 kg diazoxide and 5.0-L THF with stirring and heating to 55° C. Choline hydroxide (45% solution in methanol, 2.32 L) was added dropwise to this reaction mixture over about 2.5 hr with stirring. The temperature was maintained at 60±5° C. After addition of choline hydroxide, stirring was continued for about 30 min. The reaction mixture was clarified by in-line 10 micron filtration upon transfer to a 22-L reaction flask pre-charged with 2-L pre-filtered THF, into which was added 10-L pre-filtered MTBE dropwise. This reaction mixture was transferred to another flask which was then charged with an additional 30-L pre-filtered MTBE dropwise, with adjustment of temperature to <5° C. and stirring for about 2 hr. Diazoxide choline salt was recovered by vacuum filtration to afford 2.724 kg (94%) diazoxide choline salt (99.8%, HPLC purity), confirmed by 1H NMR, IR, and UV/Visible analysis.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=1)([O-:3])=[O:2].[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O>CS(C)=O>[CH3:14][O:13][C:6]1[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Product: COc1c(C(=O)O)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
4-Nitro-2-methoxybenzoic acid, 3.09 g, was added to 20 mL Nitric acid:Sulfuric acid 1:1, at 0° C. After addition was complete the reaction mixture was heated at 100° C. for 30 minutes. Cooled to room temperature and poured into 200 mL ice water. The aqueous layer was extracted with ethyl acetate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. This material was purified by chromatography on silica using ethyl acetate/hexane/methanol/acetic acid 5/5/1/0.1. The yellow solid obtained was used for the next step. EIMS M+242 (Exp. 242). NMR, d6 DMSO: s (1H) 8.5, s (1H) 7.95, s (3H) 4.05
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3([CH2:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:31])[CH:26]=4)[O:21]3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:31][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[O:21][C:18]1([CH2:19][CH2:20][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=3)[CH2:16][CH2:17]1)[CH2:29][C:28]2=[O:30]
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCC3(CC2)CC(=O)c2cc(Cl)ccc2O3)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H](O)c1nccc(N2CCC3(CC2)CC(=O)c2cc(Cl)ccc2O3)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18 %

Procedure:
A mixture of (R)-1′-[2-(1-butyryloxy-ethyl)-pyrimidin-4-yl]-6-chloro-spiro[chroman-2,4′-piperidin]-4-one (prepared according to the method of Example 78, Step B, 270 mg, 0.61 mmol) and lithium hydroxide hydrate (80 mg, 1.83 mmol) in a 3:1:1 mixture of tetrahydrofuran/methanol/water (5 mL) was stirred at room temperature for 1.5 h. The organic solvents were evaporated and the residue was extracted with chloroform (4×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (ethyl acetate) to give 41 mg (18%) of the title compound as a reddish foam. 1H NMR (CDCl3, 300 MHz) δ 8.19 (d, 1H), 7.82 (d, 1H), 7.44 (dd, 1H), 6.96 (d, 1H), 6.40 (d, 1H), 4.65 (q, 1H), 4.20 (app s, 2H), 3.42-3.32 (c, 2H), 2.73 (s, 2H), 2.14 (d, 2H), 1.67 (td, 2H), 1.48 (d, 3H); MS (APCI) 374, 376 (MH+); [α]D+12.6 (c, 0.5, MeOH).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([C:14](=[NH:17])OC)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:18].[NH4+:19]>C(O)C>[ClH:18].[CH2:1]([C:8]1[N:13]=[C:12]([C:14]([NH2:17])=[NH:19])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC(=N)c1cccc(Cc2ccccc2)n1
Solvent: CCO
Product: Cl
Product: N=C(N)c1cccc(Cc2ccccc2)n1

Procedure:
A mixture of methyl 6-benzyl-2-picoline imidate (0.81 g, 0.0036 moles) and ammonium chloride (0.21 g, 0.0039 moles) in ethanol (9 ml) was refluxed for 5 hours. The ethanol was removed in vacuo to give 6-benzyl-2-picoline amidine hydrochloride which was used in the final stage without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:12]([NH2:15])(=[S:14])[CH3:13]>O1CCOCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:15]=[C:12]([CH3:13])[S:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(N)=S
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(F)cc2)cs1
Yield: 73.1 %

Procedure:
Reflux a solution of 2-bromo-4′-fluoroacetophenone (10 g, 46 mmol) and thioacetamide (6.9 g, 92 mmol) in 1,4-dioxane (60 mL) for 3 h. Filter the precipitate and wash with EtOAc to give the title compound (6.5 g, 73%).
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)CC)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].C(C([C@H]1CC[C@H](C2C=CC(C#[N:38])=CC=2)CC1)CC)=C.[BH4-].[Na+].C(C1C=CC=CC=1)(=O)CC>CO>[CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:38])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: C=CC(CC)[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(C(=O)CC)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCC(=O)c1ccccc1
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1

Procedure:
A solution of 7 1 mmol of ethylmagnesium bromide (prepared from 172 mg of magnesium and 530 μl of ethyl bromide) in 20 ml of absolute tetrahydrofuran was placed at -78° C. while gassing with argon in a sulphonation flask provided with a thermometer, a dropping funnel and a serum cap and treated successively with 3 6 ml of a 0.48 M solution of dilithium tetrachlorocuprate in absolute tetrahydrofuran and with a solution of 500 mg of p-[trans-4-(3-acetoxy-trans-1-propenyl)cyclohexyl]benzonitrile in 10 ml of absolute tetrahydrofuran. After completion of the addition, the reaction mixture was warmed to -15° C., stirred at this temperature for 1.5 hours, subsequently treated with 20 ml of saturated ammonium chloride solution and stirred ar room temperature for a further 1 hour. The aqueous phase which was now deep blue, was separated and extracted twice with 50 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (0.4 g) on silica gel with ethyl acetate/petroleum ether (vol. 3.97) gave 375 mg of crude p-[trans-4-(trans-1-pentenyl)-cyclohexyl]benzonitrile which, according to analysis by gas chromatography, was contaminated to 8.5% with p-[trans-4-(trans-1-pentenyl)cyclohexyl]propiophenone and to 4.0% with p-[trans-4-(1-vinylpropyl)cyclohexyl]benzonitrile. Treatment of this crude product with an excess of sodium borohydride in methanol at 0° C. (in order to reduce the propiophenone) working-up, low-pressure chromatography (0.5 bar) on silica gel with ethyl acetate/petroleum ether (vol. 1:9) and finally recrystallization from methanol at -78° C. gave p-[trans-4-(trans-1-pentenyl)-cyclohexyl]benzonitrile in a purity of 98.6%; m.p. (C-N) 15.5° C., cl.p (N-I) 57.0° C.