Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][C@H:12]([OH:11])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: O[C@H]1CCNC1
Product: Cn1ncc([N+](=O)[O-])c1N1CC[C@H](O)C1
Yield: 96 %

Procedure:
Following Example 231, 5-Chloro-1-methyl-4-nitro-1H-pyrazole and (S)-(−)-3-hydroxypyrrolidine gave (S)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidin-3-ol (250 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 4.64-4.59 (m, 1H), 3.78 (s, 3H), 3.71-3.59 (m, 2H), 3.39 (td, J=8.8, 3.4 Hz, 1H), 3.24 (dt, J=10.2, 1.6 Hz, 1H), 2.34-2.23 (m, 1H), 2.14-2.04 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[N:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:29])[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:29][C@:21]4([CH2:20][N:19]=3)[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]4)=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2ncc(Br)nc2s1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Brc1cnc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A mixture of dimethyl 6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate (300 mg, 0.895 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (210 mg, 0.895 mmol) and cesium carbonate (600 mg, 1.79 mmol) in acetonitrile (25 mL) was heated on a 100° C. oil bath for 2 hours in an open flask, with nitrogen bubbling through the solution the entire time to help in the removal of methanethiol. After 2 hours, TLC showed the reaction to be complete, so the mixture was cooled to ambient temperature, diluted with water and concentrated in vacuo. The mixture was extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (200 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.39 (br. s., 1 H) 8.48 (s, 1 H) 4.05 (d, J=9.79 Hz, 1 H) 3.72 (d, J=9.79 Hz, 1 H) 3.42 (dd, J=15.06, 1.76 Hz, 1 H) 2.73-3.08 (m, 5 H) 2.10-2.22 (m, 2 H) 1.73-1.84 (m, J=14.09, 9.94, 4.17, 4.17 Hz, 1 H) 1.52-1.65 (m, 2 H). MS (LC/MS) R.T.=1.29; [M+H]+=394.99.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[C:16]([N:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].N12CCCN=C1CCCCC2.[I-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:19]([O:18][C:16]([N:23]1[CH2:27][CH2:26][CH:25]([NH:28][C:12]2[N:11]=[N:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:14][CH:13]=2)[CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(=O)NCCC3CC3)nn2)C1
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.400 g, 1.77 mmol), 1-Boc-3-aminopyrrolidine (0.400 g, 2.1 mmol), tetrabutylammonium bromide (0.120 g, 0.36 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.000 g, 6.00 mmol) in 1,4-dioxane (30 mL) was heated under reflux overnight. A catalytic amount of sodium iodide was added and the heating was continued for 16 hours. The solvent was removed in vacuo and the residue was washed with 1 M citric acid (50 mL) and ethyl ether (50 mL) was added. Ultrasonication of the mixture followed by filtration afforded 3-[6-(2-cyclopropylethyl-carbamoyl)pyridazin-3-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid in 81% yield (0.539 g) which was used for next step reaction without further purification.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Br[CH2:29][CH2:30][OH:31]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][CH2:30][OH:31])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: OCCBr
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCCO)ccc-2c(C(=O)OCC)c1N
Yield: 15 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 2-bromoethanol the title compound of m.p. 190-192° C. is obtained in 15% yield.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[C:47]([O:51][C:52](=[O:55])[CH2:53][NH2:54])([CH3:50])([CH3:49])[CH3:48].O>CN(C)C=O.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>[C:47]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH3:50])([CH3:49])[CH3:48]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 90 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (200 mg) and glycine t-butyl ester hydrochloride (60 mg) in dimethylformamide (3 ml), triethylamine (0.099 ml) and diethyl cyanophosphate (72 ml) were added, followed by stirring at room temperature for 17 hours. After addition of water, the reaction mixture was extracted with chloroform. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium. hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to yield the title compound (206 mg, yield 90%) as a wax-like substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]=[C:5]1[CH2:8][CH:7]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:6][CH:7]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8]1
Reactant: COC(=O)C=C1CC(COCc2ccccc2)C1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1CC(COCc2ccccc2)C1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
(3-Benzyloxymethyl-cyclobutylidene)-acetic acid methyl ester (5.4 g, 21.9 mmol) were dissolved in 80 ml methanol and cooled to 0-5° C. NiCl2 (2.53 g, 19.5 mmol) and NaBH4 (4.14 g, 109.6 mmol) were added slowly and the reaction mixture stirred for 1 hour at 0-5° C. The reaction mixture was quenched with 1N HCl and extracted two times with dichloromethane. The organic extract was washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (3.0 g, 55%) was obtained as a colourless liquid and used without any further purification for the next step. MS: m/e=249.1 (M+H+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1.[H-].[Na+]>CN(C)C=O>[N+:29]([C:17]1[CH:16]=[CH:15][C:14]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])([O-:31])=[O:30]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCC2)ccc1[N+](=O)[O-]

Procedure:
In a similar manner to that described in Reference Example 27, a reaction was carried out using 2-pyrrolidinophenol (1.88 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (3.34 g), sodium hydride (55 wt. %, 0.52 g) and anhydrous N,N-dimethylformamide (22 ml) and the reaction mixture was purified to afford t-butyl N-[2-nitro-5-(2-pyrrolidinophenoxy)phenyl]-N-methylcarbamate, of which Rf value was 0.25 in thin layer chromatography on a silica gel plate using c-hexane/ethyl acetate=10/1. In a similar manner to that described in Reference Example 27, a reaction was carried out using this product, palladium on carbon (10%, 0.45 g) and toluene/methanol=7/3 (50 ml) and the reaction mixture was purified to give the title compound (3.0 g).
Reaction SMILES: [CH3:1][SiH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Rh]>[CH3:1][Si:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCC[SiH2]C
Reactant: C=CCCCCCC
Agent: [Rh]
Product: CCCCCCCCCC[Si](C)(CCCCCCCC)CCCCCCCC
Reaction time: 0.5 h

Procedure:
There was added 40 grams of methyldecylsilane for a period of 25 minutes to a mixture of 95.5 parts of 1-octene and 8 parts per million of rhodium catalyst as prepared in Example 2. A slow stream of air bubbled into the solution prior to the addition of the methyldecylsilane. The octene solution containing the rhodium catalyst was also preheated to a temperature of 80° C. After an additional 30 minutes of heating, an additional amount of rhodium catalyst was added to the mixture for a final total of 17 parts per million. After 1/2 hour, a quantitative yield of methyldecyldioctylsilane was obtained.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[N+:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:11]=1)([O-:14])=[O:13]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1NC(=O)CBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1NC(=O)CN1CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(2-tert-butyl-5-nitro-phenyl)-acetamide (2.58 g, 8.2 mmol) and K2CO3 (2.27 g, 16.4 mmol) were combined in a round bottom flask under N2. THF (100 mL) was added and the mixture cooled to 0° C. under N2. Piperidine (1.05 g, 12.3 mmol) was added to the mixture and the mixture was gradually warmed to RT with stirring overnight. The reaction was quenched by filtering it under vacuum and concentrating the filtrate under reduced pressure. The recovered material was eluted through a column of silica gel with a 5 to 50% EtOAc:Hexanes linear gradient giving a brown solid.
Reaction SMILES: [NH2:1][C:2]([NH2:24])=[N:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16](Cl)[CH:17]=2)=[C:7]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=1.[CH3:25]S(C1C=C(C=CC=1OC1C=NC=CC=1O)C(OC)=O)(=O)=O>>[NH2:1][C:2]([NH2:24])=[N:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[CH3:25])=[C:7]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=1
Reactant: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1Oc1cncc(Cl)c1
Reactant: COC(=O)c1ccc(Oc2cnccc2O)c(S(C)(=O)=O)c1
Product: Cc1ccncc1Oc1ccc(C(=O)N=C(N)N)cc1S(C)(=O)=O

Procedure:
N-diaminomethylene-3-methylsulfonyl-4-(5-chloro-3-pyridyloxy)benzamide, m.p. 233°; with methyl 3-methylsulfonyl-4-(4-hydroxy-3-pyridyloxy)benzoate,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2OC(=O)[S:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]([C:21]([O:23][CH3:24])=[O:22])#[C:16][C:17]([O:19][CH3:20])=[O:18]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21]([O:23][CH3:24])=[O:22])[S:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=c1oc(-c2ccc(Cl)c(Cl)c2)ns1
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2ccc(Cl)c(Cl)c2)c1C(=O)OC
Yield: 70.7 %

Procedure:
5-(3,4-Dichlorophenyl)-1,3,4-oxathiazol-2-one (99.2 g, 0.4 mol) and dimethyl acetylenedicarboxylate (113.5 g, 0.8 mol) were heated in 240 ml of chlorobenzene at reflux for 47 hours. The product, from hot methanol, was recrystallized twice from hot methanol to give 97.8 g (0.283 mol, 70.7%) of white solid, m.p. 105°-107°.
Reaction SMILES: FC1C=CC(N)=C(C2C=CC3C(=CC=C(OC)C=3)C=2)C=1.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][N:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[C:48]([F:61])[CH:47]=2)=[C:41]([C:62]2[CH:71]=[CH:70][C:69]3[C:64](=[CH:65][CH:66]=[C:67]([O:72]C)[CH:68]=3)[CH:63]=2)[CH:40]=1>>[F:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][N:55]3[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]3)=[C:48]([F:61])[CH:47]=2)=[C:41]([C:62]2[CH:63]=[C:64]3[C:69](=[CH:70][CH:71]=2)[CH:68]=[C:67]([OH:72])[CH:66]=[CH:65]3)[CH:40]=1
Reactant: COc1ccc2cc(-c3cc(F)ccc3Nc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Agent: COc1ccc2cc(-c3cc(F)ccc3N)ccc2c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc2cc(-c3cc(F)ccc3Nc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Yield: 82.6 %

Procedure:
Synthesized from 4-fluoro-2-(6-methoxynaphthalen-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [4-fluoro-2-(6-methoxynaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]amine (404 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (324 mg).
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[C:67]([O:71][C:72]([N:74]([C:82]1[S:83][C@@H:84]2[CH2:90][O:89][CH2:88][CH2:87][C@:85]2([C:91]2[CH:96]=[CH:95][CH:94]=[C:93](Br)[CH:92]=2)[N:86]=1)C(OC(C)(C)C)=O)=[O:73])([CH3:70])([CH3:69])[CH3:68]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:1](=[N:14][C:93]1[CH:92]=[C:91]([C@:85]23[CH2:87][CH2:88][O:89][CH2:90][C@H:84]2[S:83][C:82]([NH:74][C:72](=[O:73])[O:71][C:67]([CH3:69])([CH3:68])[CH3:70])=[N:86]3)[CH:96]=[CH:95][CH:94]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cccc(Br)c3)CCOC[C@H]2S1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N=C(c4ccccc4)c4ccccc4)c3)CCOC[C@H]2S1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Benzophenone imine (244 μL), BINAP (60.6 mg), tris(dibenzylideneacetone)dipalladium (0) (44.6 mg) and sodium tert-butoxide (233 mg) were added to a solution of (±)-N,N-bis(tert-butoxycarbonyl)[(3aS*,7aR*)-7a-(3-bromophenyl)-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazol-2-yl]amine (250 mg) in toluene (20 mL). After replacement with nitrogen, the mixture was stirred at 85° C. for four hours. The reaction solution was returned to room temperature, and water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (165 mg).
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:15][S:16](Cl)(=[O:18])=[O:17].[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[CH3:15][S:16]([O:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12])(=[O:18])=[O:17]
Reactant: CN(CCO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(CCOS(C)(=O)=O)Cc1ccccc1

Procedure:
N-Benzyl-N-methyl-ethanolamine (20.73 g), 61.94 g of toluene and 83.41 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 300-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.8° C. Then, 31.68 g of methanesulfonyl chloride was added dropwise over 3 hours and 17 minutes at a flask inside temperature of 5 to 10° C. Water (33 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of N-benzyl-N-methyl-ethanolamine methanesulfonate was thus obtained in a yield of 68.8 mole percent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO[C:19](=O)[CH:20]1[CH2:25][CH:24](I)CCN1.[OH-].[Li+]>CN(C=O)C.C1COCC1>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1)[CH2:20][CH2:25][CH3:24]
Reactant: COC(=O)C1CC(I)CCN1
Reactant: O=C(O)c1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOc1ccnc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To 4-hydroxypyridine-2-carboxylic acid (200 mg, 1.4 mmol) in DMF (2 mL), potassium carbonate (397 mg, 2.8 mmol) was added followed by n-bromobutane (197 mg, 1.4 mmol), warmed at 60° C. for overnight. The solvent was removed to obtain the crude ester product. The crude ester (360 mg, 1.4 mmol) was dissolved in THF (4 mL), lithium hydroxide (72 mg, 1.7 mmol) was added, and the reaction mixture stirred at room temperature for 2 h. The residue obtained on removal of solvent was purified by silica gel chromatography using 10% MeOH in DCM to provide 4-butoxypyridine-2-carboxylic acid 15a (R10=butyl) (100 mg, 43%). 1H NMR (300 MHz, CD3OD) δ 8.37 (d, J=6.0, 1), 7.63 (d, J=2.7, 1), 7.07 (dd, J=2.7, 6.0, 1), 4.15 (t, J=6.6, 2), 1.82 (m, 2), 1.54 (m, 2), 1.01 (t, J=7.5, 3). MS (ES−): 194 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[O:39]1CCCC1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:39])[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:27])([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2O)c(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a mixture of 39.9 g. (80 mmols.) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,2,5,6-tetrahydropyridine and 4.8 g. (115 mmols.) of sodium borohydride in 50 ml. of tetrahydrofuran is added 21.6 ml. (180 mmols.) of borontrifluoride etherate complex in 40 ml. of tetrahydrofuran during a 2 hour period at 0°-5° C. Stirring is continued 2 hours longer at 25° C. The reaction mixture is cooled in ice and quenched with 6.5 ml. of water and then 20 ml. of 2N sodium hydroxide and 20 ml. of 30% hydrogen peroxide are added dropwise. After several minutes stirring the reaction is cooled and 20 ml. of concentrated hydrochloric acid is added dropwise. The reaction mixture is partially evaporated and then made basic with 6N sodium hydroxide. The concentrated mixture is extracted with 250 ml. of ether, the ether extract washed with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 400 g. of silica gel eluted with 50% ether-cyclohexane to yield the title compound.
Reaction SMILES: C(O[CH:5]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16](OC(=O)C)[CH:15]2[CH:6]1[C:7](=[O:36])[C:8]1[C:9]3([S:35][CH2:34][CH2:33][S:32]3)[CH2:10][CH:11]([C:28]([O:30][CH3:31])=[O:29])[CH2:12][C:13]=1[C:14]2=[O:27])(=O)C>C1(C)C(C)=CC=CC=1>[O:36]=[C:7]1[C:6]2[C:15](=[CH:16][C:17]3[C:22]([CH:5]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:27])[C:13]2[CH2:12][CH:11]([C:28]([O:30][CH3:31])=[O:29])[CH2:10][C:9]3([S:32][CH2:33][CH2:34][S:35]3)[C:8]1=2
Reactant: COC(=O)C1CC2=C(C(=O)C3C(OC(C)=O)c4ccccc4C(OC(C)=O)C3C2=O)C2(C1)SCCS2
Solvent: Cc1ccccc1C
Product: COC(=O)C1CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)SCCS2
Yield: 97.4 %

Procedure:
(a) A solution of 32 mg (0.06 mmol) of methyl rac-1',2',3',4',5',5a',6',11',11a',12'-decahydro-6',11'-diacetoxy-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate in 2 ml of dry xylene was stirred and heated under reflux under an atmosphere of nitrogen for 20 hours. The solution was then evaporated to dryness to give 24 mg (97%) of methyl rac-1',2',3',4',5',12'-hexahydro-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate in the form of a bright yellow solid of melting point 216° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[NH:15][C:14]2([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][F:31].[H-].[Na+]>C(OCC)(=O)C>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[N:15]([CH2:29][CH2:30][F:31])[C:14]2([CH3:20])[CH3:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)NC(=O)c2c(N(Cc3ccccc3)Cc3ccccc3)cccc21
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)c2cccc(N(Cc3ccccc3)Cc3ccccc3)c2C(=O)N1CCF
Temperature: 25 °C
Reaction time: 4 h

Procedure:
67 mg (0.188 mmol) 7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one are dissolved in 1 ml (7.877 mmol) 1-bromo-2-fluoroethane and combined with 52 mg (0.376 mmol) sodium hydride. After 4 h stirring at ambient temperature the mixture is diluted with ethyl acetate and extracted three times with 1 M hydrochloric acid. The combined organic phases are dried and the solvent is eliminated in vacuo.