Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH2:22]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11].[H-].[Na+].N1C(=O)C2N(C)C=NC=2N(C)C1=O.BrCCCCCCC=C>CS(C)=O.O>[CH2:8]([N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:22]
Reactant: Cn1cnc2c1c(=O)n(CCCCCCC(O)CO)c(=O)n2C
Agent: C=CCCCCCCBr
Agent: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
1-(7,8-Dihydroxyoctyl)-3,7-dimethylxanthine was used as an intermediate for the synthesis of inventive compound no. 1514 (example 12). To a suspension of sodium hydride (580 mg, 24.2 mmol) in dimethylsulfoxide (100 ml) was added theobromine (3.96 g, 22.0 mmol). After stirring for 30 min, 8-bromo-1-octene (3.96 g, 22 mmol) was added and the mixture was stirred for 16 hr. The mixture was poured into water (200 ml) and extracted with dichloromethane (3×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate, and the solvent was evaporated under vacuum to give 1-(7-octenyl)-3,7-dimethylxanthine (6.22 g, 97% yield) as an oil which solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:27])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[C:28](OCC)(=O)C.CO>[Pd]>[Cl:27][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([Cl:1])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:28])=[C:19]([CH:24]([CH3:25])[CH3:26])[CH:18]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)ccc1O
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1C(C)C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Step D (31 mg, 0.072 mmol) was dissolved in ethyl acetate/methanol (1 ml/1 ml) and placed in a hydrogenation bottle with 10% palladium on carbon (90 mg). The mixture was placed on Parr shaker for two hours under 50 p.s.i. of hydrogen, then filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate/methanol. The combined filtrate was concentrated to give the title compound (26 mg) as a clear, viscous oil that was used in the next step without purification. MS (APCI−) Calc: 439.0, Found: 438.1 (M−1).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=O)[C:6]([C:10]([NH2:12])=O)=[N:5][N:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[N:8]=[C:3]([S:2][CH3:1])[N:4]=[N:5][C:6]=1[C:10]#[N:12]
Reactant: CSc1nnc(C(N)=O)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nnc(C#N)c(Cl)n1

Procedure:
A solution of 500 mg (2.7 mmol) of 3-methylsulfanyl-5-oxo-4,5-dihydro-[1,2,4]triazine-6-carboxylic acid amide (J. J. Huang, J. Org. Chem. 1985, 50, 2293-2298; H. Wang et al., Hua Hsueh Hsueh Pao 1964, 30(2), 183-192; CA Vol. 61, 8311b) in 38 ml (408 mmol) of phosphorus oxychloride was heated to reflux during 1.5 h. After cooling of the dark brown reaction mixture, the excess of phosphorus oxychloride was evaporated under reduced pressure. To destroy residues of phosphorus oxychloride and to neutralize the reaction mixture, the resulting red-brown oily residue was dissolved in 15 ml of toluene and the solution added to an ice-cold saturated aqueous solution of sodium hydrogencarbonate. The organic phase was diluted with 100 ml of dichloromethane, separated from the aqueous phase, dried over sodium sulfate, and evaporated under reduced pressure. The resulting 5-chloro-3-methylsulfanyl-[1,2,4]triazine-6-carbonitrile was obtained as a brown oil and was used in the following reactions without further purification.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[F:12][C:13]1[CH:14]=[C:15]([NH2:22])[C:16](=[CH:20][CH:21]=1)[C:17]([OH:19])=[O:18]>ClCCl>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:22][C:15]1[C:16](=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=1)[C:17]([OH:19])=[O:18])=[O:11])([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: ClCCl
Product: O=C(O)c1ccc(F)cc1NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of phthalic anhydride (4.8 g) and 4-fluoroanthranilic acid (5 g) in dichloromethane (100 ml) was stirred at room temperature for 48 hours and the solid collected and washed with dichloromethane to give N-(2-carboxybenzoyl)-4-fluoroanthranilic acid, m.p. 187°-188°. (Compound 1).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[F:35][C:32]([F:33])([F:34])[O:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[N:21]=[CH:20][C:19]([CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[CH:9][N:8]4[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=3)=[CH:24][CH:23]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(OCc3ccc(-c4ccc(OC(F)(F)F)cc4)nc3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3ccc(-c4ccc(OC(F)(F)F)cc4)nc3)cc21

Procedure:
In analogy to the procedure described in example 5 g], {6-[6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain the title compound as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[H-].[Na+].[CH3:22][O:23][CH2:24]Cl>CN(C=O)C>[Br:1][C:2]1[N:6]([CH2:22][O:23][CH3:24])[C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COCCl
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1c(Br)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 66 %

Procedure:
Methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared as in Example 7, Step 1) was dissolved in DMF and sodium hydride (1.4 eq.) was added. The mixture was stirred at RT until evolution of gas had ceased, then chloromethyl methyl ether (excess) was added and stirring was continued. After 5 h all volatiles were evaporated i. vac. and the residual material was filtered through silica gel (PE:Et2O, 12:1). The product was obtained as a colourless solid (66%). 1H-NMR (400 MHz, CDCl3, 300 K, δ): 7.73 (s, 1H), 5.41 (s, 2H), 3.90 (s, 3H), 3.32 (s, 3H), 2.73-2.67 (m, 1H), 1.90-1.76 (m, 5H), 1.65-1.58 (m, 2H), 1.47-1.29 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3](=[N:19][OH:20])[CH2:4][C:5]([C:7]1[C:16](=[O:17])[NH:15][C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[C:8]=1[OH:18])=O>FC(F)(F)C(O)=O>[OH:18][C:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[NH:15][C:16](=[O:17])[C:7]=1[C:5]1[O:20][N:19]=[C:3]([C:2]([F:22])([F:21])[F:1])[CH:4]=1
Reactant: O=C(CC(=NO)C(F)(F)F)c1c(O)c2nccnc2[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2nccnc2c(O)c1-c1cc(C(F)(F)F)no1

Procedure:
A suspension of 4,4,4-trifluoro-1-(8-hydroxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-7-yl)-butane-1,3-dione 3-oxime (Example 6.4) (0.068 g) in trifluoroacetic acid (“TFA”) (0.5 ml) was heated to reflux for 7 hours. The solid was isolated by filtration and washed with diethyl ether and then dried. The solid was heated to reflux again in trifluoroacetic acid (“TFA”) (2.0 ml) for 2 days and worked up similarly to give Compound No. B10 of Table B (0.050 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][NH:7][C:6]2=[N:10][CH:11]=[CH:12][C:5]=12.[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C)C(=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (36.141 g, 903.62 mmol) in N,N-dimethylacetamide (118 mL) at −5° C. (ice/salt bath) was added a dark solution of 4-chloropyrrolo[2,3-d]pyrimidine (119.37 g, 777.30 mmol) in N,N-dimethylacetamide (237 mL) slowly. The flask and addition funnel were rinsed with N,N-dimethylacetamide (30 mL). A large amount of gas was evolved immediately. The mixture became a slightly cloudy orange mixture. The mixture was stirred at 0° C. for 60 min to give a light brown turbid mixture. To the mixture was slowly added [2-(trimethylsilyl)ethoxy]methyl chloride (152.40 g, 914.11 mmol) and the reaction was stirred at 0° C. for 1 h. The reaction was quenched by addition of 12 mL of H2O slowly. More water (120 mL) was added followed by methyl tert-butyl ether (MTBE) (120 mL). The mixture was stirred for 10 min. The organic layer was separated. The aqueous layer was extracted with another portion of MTBE (120 mL). The organic extracts were combined, washed with brine (120 mL×2) and concentrated under reduced pressure to give the crude product 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine as a dark oil. Yield: 85.07 g (97%); LC-MS: 284.1 (M+H)+. It was carried to the next reaction without purification.
Reaction SMILES: [C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:36])/[C:10](=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)/[CH2:11][CH2:12][CH2:13][O:14]C2CCCCO2)[CH:2]=1>CO>[C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:36])/[C:10](=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)/[CH2:11][CH2:12][CH2:13][OH:14])[CH:2]=1
Reactant: COc1cc(/C=C(\CCCOC2CCCCO2)C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Solvent: CO
Product: COc1cc(/C=C(\CCCO)C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
To the methanol (5 mL) solution of (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-5-(tetrahydropyran-2-yloxy) valeric acid (biphenyl-3-ylmethyl)amide (168 mg), Dow-X™50W X-8 (300 mg) was added, and the reaction solution was agitated at 45° C. for 5 hours. The resin was filtered off, the ammonia water (1 mL) was added to the filtrate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:ethyl acetate→ethyl acetate:methanol=9:1), and 120 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: NC1CC1
Product: Fc1ccc(CNC2CC2)cc1

Procedure:
Synthesized according to typical procedure J from 4fluorobenzaldehyde and cyclopropylamine.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH2:41])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH3:31])[CH3:30]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 621.0 [(M−H)−]; mp 257° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1>O>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 24 h

Procedure:
10 Grams of p-hydroxybenzoic acid and 15 g of decanoic acid chloride were stirred at room temperature, and 7.2 g of pyridine was dropwise added. After the mixture was stirred for 1 day, a reaction product was poured into water, and an organic layer was extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid and dried over anhydrous sodium sulfate, the solvent was distilled off, and then residue was washed with n-hexane and then dried to give a crude end product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31](C(OC(C)(C)C)=O)[C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[NH:31][C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2ccoc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccoc2c1
Yield: 80.8 %

Procedure:
A mixture of 6-methylbenzofuran (3.44 g, 0.026 mol), N-bromosuccinimide (4.63 g, 0.026 mol), dibenzoyl peroxide (trace) and carbon tetrachloride (50 cm3) was refluxed for 5 hr. The mixture was filtered and the solvent was removed from the filtrate. The residue was distilled to give 6-bromomethylbenzofuran (4.38 g, 0.021 mol, 80.0%) b.p. 84°-88° C./0.7 mm Hg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([CH:23]4[CH2:25][CH2:24]4)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: C[C@]12CCc3c(Br)cccc3[C@H]1CN(Cc1ccccc1)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@]12CCc3c(C4CC4)cccc3[C@H]1CN(Cc1ccccc1)C2
Yield: 56.1 %

Procedure:
cis-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.421 mmol, 150 mg) was dissolved in dioxane (2 ml) and water (0.7 ml). Cyclopropylboronic acid (0.631 mmol, 54.2 mg), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.021 mmol, 15.40 mg) and potassium carbonate (0.631 mmol, 87 mg) were added and the reaction mixture was irradiated at 160° C. in a microwave reactor for 30 minutes. The reaction mixture was diluted with DCM and water. The phases were separated and DCM extract was concentrated in vacuo to give a crude residue that was purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford cis-2-benzyl-6-cyclopropyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (75 mg), m/z: 318.2 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:17]3[CH2:18][CH2:19][N:20]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(c1ccc(-c2cccc(Cl)c2)cc1)C1CCNCC1
Reactant: Clc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(-c2cccc(Cl)c2)cc1)C1CCN(c2ncccn2)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
(3′-Chloro-biphenyl-4-yl)-piperidine-4-yl-methanone hydrochloride (2, 23.4 kg, 69.6 mol), 2-chloropyrimidine (8.9 kg, 1.3 equiv), and 325-mesh potassium carbonate (25 kg, 3 equiv) were mixed in acetonitrile (211 L) in a 100-gallon reactor. The batch was heated with agitation at 55-65° C. for 16 h. The batch was then cooled to 20-30° C., followed by the addition of water (70 L) and further stirred for 15 min. The batch was transferred to a 300-gallon reactor and rinsed with water (360 L) to afford a thick white suspension. After stirring for 2 h, the batch was filtered and washed with water (2×70 L) and dried to constant weight at 45-55° C. to afford crude compound 3 (23.5 kg, 89.5% yield, >99% purity) as a white crystalline solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=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.[CH3:48][N:49]([CH3:53])[CH2:50][CH2:51][NH2:52]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:52][CH2:51][CH2:50][N:49]([CH3:53])[CH3:48])=[O:5]
Reactant: O=C(O)CCl
Reactant: CN(C)CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)CCl
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-chloroacetic acid (214 mg, 2.27 mmol), PyBOP® (1.18, 2.27 mmol), DIEA (1.18 mL, 6.81 mmol) in CH2Cl2 (1 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of N1,N1-dimethylethane-1,2-diamine (249 μL, 2.27 mmol) and CH2Cl2 (4 mL). The reaction mixture was stirred at RT for 1.5 h. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product 2-chloro-N-(2-(dimethylamino)ethyl)acetamide.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[Na].[C:14](#[N:17])[CH:15]=[CH2:16]>C(O)(C)(C)C>[C:14]([CH2:15][CH2:16][O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)#[N:17]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: C=CC#N
Agent: [Na]
Solvent: CC(C)(C)O
Product: CN1C(C)(C)CC(OCCC#N)CC1(C)C
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To 51 parts of 1,2,2,6,6-pentamethylpiperidin-4-ol a solution of metallic sodium in two parts of tert.butanol was added. 52.5 parts of acrylonitrile was dropped in with rapid stirring. After standing for two days at room temperature the mixture was heated to 80° C. for two hours and distilled under reduced pressure yielding 4-(2'-cyanoethoxy) 1,2,2,6,6-pentamethylpiperidine with a boiling point of 172°-4° C. at 17 mm Hg. This sample was identical to that prepared under Example 88a.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:26]([O-])([N+]([O-])=O)=[O:27]>>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: COc1ccc(CN(C(=O)NCCCl)C2OC[C@H](O)[C@H](O)[C@H]2O)cc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: COc1ccc(CN(C(=O)N(CCCl)N=O)C2OC[C@H](O)[C@H](O)[C@H]2O)cc1
Yield: 62.7 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-(p-methoxybenzyl)-3-(L-arabinopyranosyl)urea and 5.0 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(p-methoxybenzyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:15]=[C:16]([C:22]6[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=6)[S:17][C:18]=5[CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:7]=[N:6]2)[CH2:2]1.CO.C(N(CC)C(C)C)(C)C.[CH3:44][C:45]1([O:48][CH2:47]1)[CH3:46]>>[CH:28]([N:23]1[C:22]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:12]4[CH:11]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([CH:3]6[CH2:4][N:1]([CH2:44][C:45]([CH3:47])([OH:48])[CH3:46])[CH2:2]6)[CH:9]=5)[CH:32]=[CH:31][C:13]=4[C:14]=3[N:15]=2)=[N:26][C:25]([CH3:27])=[N:24]1)([CH3:29])[CH3:30]
Reactant: CC1(C)CO1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CNC5)c4)ccc2-3)n(C(C)C)n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CN(CC(C)(C)O)C5)c4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a slurry of 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.232 g, 0.000519 mol) in methanol (3.0 mL, 0.074 mol) was added N,N-Diisopropylethylamine (0.108 mL, 0.000623 mol) then isobutylene oxide (0.330 mL, 0.0037 mol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and purified by reverse-phase HPLC to give 480 (24.3 mg) as a colorless solid. MS (ESI+) 520.2. 1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.31 (d, J=8.3, 1H), 8.01 (s, 1H), 7.47 (dd, J=8.3, 1.8, 1H), 7.35 (d, J=1.8, 1H), 5.86-5.68 (m, 1H), 4.97 (p, J=6.9, 1H), 4.39 (t, J=5.0, 2H), 4.11 (s, 1H), 3.79 (dd, J=8.0, 7.3, 2H), 3.49 (dd, J=8.0, 6.8, 2H), 3.44 (t, J=5.0, 2H), 2.44 (s, 2H), 2.32 (s, 3H), 1.53 (d, J=6.6, 6H), 1.08 (s, 6H).
Reaction SMILES: O1CCCCC1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.S(O[Si](C)(C)C)(O[Si](C)(C)C)(=O)=O.N1C=CC=CC=1>CO.C(OCC)C.ClCCl>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C@H:11]3[CH2:12][CH2:13][C@H:8]([OH:7])[CH2:9][CH2:10]3)=[CH:19][CH:18]=2)=[CH:25][CH:24]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)O[Si](C)(C)C
Solvent: c1ccncc1
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.2 g of trans-4-(4'-decyl-4-biphenylyl)cyclohexyl tetrahydropyranyl ether in 40 ml of methanol and 2 ml of diethyl ether was treated with a solution of 7.3 mg of bistrimethylsilyl sulfate in 2 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours and then treated with 0.2 ml of pyridine. Subseguently, the reaction mixture was concentrated and the residue was then taken up in 50 ml of dichloromethane, washed twice with water, dried over magnesium sulfate, filtered and again concentrated. The residue was purified by chromatography on silica gel with toluene/ethyl acetate (vol. 9:1). Recrystallization from methanol gave 0.5 g of trans-4-(4'-decyl-4-biphenylyl)cyclohexanol.