Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[CH3:15][Si:16]([CH3:19])(Cl)[Cl:17]>CCCCCC>[CH3:15][Si:16]([Cl:17])([CH3:19])[CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[Si](C)(Cl)C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.9 %

Procedure:
In a 2-liter flask were charged 50 g (0.43 mol) of indene and 600 ml of dry n-hexane, to which was dripped down 270 ml of a hexane solution of 1.6 M n-butyllithium at 0° C. The mixture was stirred at room temperature for 10 hours, to which was added 111 g (0.86 mol) of dimethyidichlorosilane and the mixture was stirred as was at room temperature for 3 hours. After it was filtered through a G-4 filter, the reaction mixture was distilled under reduced pressure to remove volatile components. The crude product thus obtained was purified by distillation under reduced pressure (100° C., 7 mmHg) under argon atmosphere. As a result, 78 g of the target compound was obtained. Yield: 87%.
Reaction SMILES: [CH2:1](O)[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5](O)[C@@H:4](O)[C@@H:3]1O.S([O-])([O-])(=O)=O.[NH4+:29].[NH4+:30].OP([O-])(O)=O.[K+].CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO.Cl.[Cl-].C(=O)([O-])[O-].[Ca+2].OC(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O>>[NH2:29][C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][CH2:2][CH2:1][NH2:30]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: [NH4+]
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Product: NCCCC[C@H](N)C(=O)O
Temperature: 31.5 °C
Reaction time: 72 h

Procedure:
Strains of Brevibacterium lactofermentum AJ 12593 (FERM BP-3240) were inoculated in a culture medium comprising 80 g/L of waste molasses as a sucrose, 50 g/L of ammonium sulfate, 1 g/L of KH2PO4, 1 g/L of MgSO4.7H2O, 10 mg/L of soybean protein hydrolyzate (as nitrogen), 0.1 mg/L of thiamine hydrochloride, 50 g/L of calcium carbonate and 0.3 mg/L of biotin. The mixture was cultured while agitating at 31.5° C. for 72 hours to form a L-lysine fermentation broth. Then, the resultant fermentation broth was dried using a drum dryer to form 5 kg of a dried flaky product having the composition below.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](O)=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1>O1CCCC1.O>[F:35][C:12]1[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([CH2:22][OH:23])[CH:20]=2)(=[O:17])=[O:18])[C:13]=1[C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(CO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 83.2 %

Procedure:
To a solution of 3-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}benzoic acid (256 mg) in tetrahydrofuran (2 mL) was added a 1.9 mol/L toluene solution (0.53 mL) of borane dimethylsulfide complex at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to give the title compound as a pale-yellow oil (yield 207 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.[NH2:14][NH2:15]>O>[NH2:1][C:2]1[C:3]([C:9]([NH:14][NH2:15])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: NN
Solvent: O
Product: NNC(=O)c1nc(Br)cnc1N
Temperature: 100 °C
Yield: 100.4 %

Procedure:
A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (5 g, 21.55 mmol) and hydrazine hydrate (5.397 g, 5.245 mL, 107.8 mmol) were heated to 100° C. for 1.5 hours. Water was added and the product collected by filtration, washed with methanol and dried to give 3-amino-6-bromo-pyrazine-2-carbohydrazide as a yellow solid (5.02 g, 100.4% Yield). MS (ES+) 233.78
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]3)([O:3]C)=[O:2].O.O[Li].O.OS([O-])(=O)=O.[Na+]>O1CCOCC1>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]3)([OH:3])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(=O)OC(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@H]2[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 17β-carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one (15.4 g, 36 mmol), from part E, in dioxane (150 mL) and water (100 mL) is treated with LiOH.H2O (3.31 g, 79 mmol) and stirred overnight in a water bath. The reaction is poured into saturated aqueous NaHSO4 (150 mL), extracted with methylene chloride (3×100 mL), extracts washed with saturated aqueous NaCl, dried over MgSO4 and concentrated to a volume of 100 mL. At this point crystals begin to form and 2:1 hexanes/ethyl acetate (50 mL) is added, the mixture triturated, cooled to room temperature and 17β-carboxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one collected as a fluffy white powder; yield: 9.44 g (63%); m.p. 215°-216° C. Anal. Calcd. for C24H35NO5.1/4H2O; C, 68.30; H, 8.48; N, 3.32. Found: C, 68.45; H, 8.41; N, 3.28.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1([F:38])[O:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]3([C:16]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=5)[C:28]([OH:30])=[O:29])[C:22]([C:34](OC)=[O:35])=[CH:21][CH:20]=4)=[O:17])[CH2:15][CH2:14]3)=[CH:12][C:6]=2[O:5]1>C1COCC1>[F:38][C:4]1([F:3])[O:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]3([C:16]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=5)[C:28]([OH:30])=[O:29])[C:22]([CH2:34][OH:35])=[CH:21][CH:20]=4)=[O:17])[CH2:14][CH2:15]3)=[CH:12][C:6]=2[O:5]1
Reactant: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2CO)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 39.6 %

Procedure:
NaBH4 (53 mg, 1.4 mmol) was added to a solution of 3-(6-(1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-(methoxycarbonyl)pyridin-2-yl)benzoic acid (140 mg, 0.28 mmol) in THF (3 mL). The reaction was stirred at 50° C. for 5 hours. Additional NaBH4 (53 mg, 1.4 mmol) was added and the reaction was stirred at 50° C. overnight. The reaction was quenched by the addition of water and the reaction mixture was partitioned between CH2Cl2 and 1N HCl. The organic layer was dried (MgSO4) and concentrated. CH2Cl2 was added to the residue and a precipitate formed which was filtered to obtain the product as a white solid (52 mg, 40%). ESI-MS m/z calc. 468.1, found 469.5 (M+1)+. Retention time 1.64 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.06 (d, J=1.5 Hz, 1H), 8.01-7.93 (m, 3H), 7.76 (d, J=7.5 Hz, 1H), 7.57-7.54 (m, 2H), 7.40-7.34 (m, 2H), 5.33 (s, 1H), 4.38 (s, 2H), 1.53-1.51 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=O.[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18].CCN=C=NCCCN(C)C>CN(C)C=O.C(OCC)C>[CH2:16]([N:19]([CH2:20][CH2:21][CH3:22])[C:13]([CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)=[O:15])[CH2:17][CH3:18]
Reactant: CCCNCCC
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCN(CCC)C(=O)Cc1c[nH]c2ccc(OC)cc12
Reaction time: 12 h
Yield: 51.2 %

Procedure:
A solution of 5-methoxyindole-3-acetic acid (500 mg, 2.44 mmol) in 4.8 mL of N,N-dimethylformamide was added di-n-propylamine (0.60 mL, 7.2 mmol) and EDCI (1.90 g, 9.6 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 12 h, the reaction mixture was diluted with diethyl ether, and washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (360 mg, 51%).
Reaction SMILES: [O:1]([CH2:5][CH3:6])[C:2]([S-:4])=[S:3].[K+].O.[CH2:9]([S:11][CH:12]1[N:15]([CH:16](Cl)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:31])[CH2:13]1)[CH3:10]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[CH2:9]([S:11][CH:12]1[N:15]([CH:16]([S:3][C:2]([O:1][CH2:5][CH3:6])=[S:4])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C:14](=[O:31])[CH2:13]1)[CH3:10]
Reactant: CCOC(=S)[S-]
Reactant: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=S)SC(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SCC
Reaction time: 1 h

Procedure:
To a stirred mixture of 3.2 g. of potassium ethyl xanthate, 5.4 g. of benzyltriethylammonium chloride, 100 ml. of water and 50 ml. of dichloromethane, at 0° C., was added a solution of 7.12 g. of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-chloroacetate in 75 ml. of dichloromethane. Stirring was continued at 0°-5° C. for 1 hour, and then the organic phase was removed. The aqueous phase was extracted with 100 ml. of dichloromethane, and then the combined dichloromethane layers were washed successively with 75 ml. of dilute hydrochloric acid, 75 ml. of saturated aqueous sodium bicarbonate and 75 ml. of water. The dichloromethane solution was dried with anhydrous sodium sulfate and evaporated to dryness in vacuo, and the residue was purified by column chromatography on 200 g. of silica gel, eluting with 95:5 chloroform-ethyl acetate. The product containing fractions were combined and concentrated in vacuo to give 4.3 g of the title compound. The IR spectrum (chloroform) showed an absorption at 5.66 microns. The NMR spectrum (deuterochloroform) showed peaks at 1.02-1.6 (m, 6H); 2.35-3.65 (m, 4H); 4.4-5.1 (m, 3H); 5.3 (s, 2H); 6.3 and 6.4 (ss, 1H); 7.4 (d, 2H); and 8.2 (d, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14](Cl)[C:15]([F:18])([F:17])[F:16].Cl.[CH3:21][NH:22][CH3:23].C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]([N:22]([CH3:23])[CH3:21])[C:15]([F:18])([F:17])[F:16]
Reactant: CNC
Reactant: FC(F)(F)C(Cl)=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
First, 0.34 g (1.0 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoroacetoimidoyl chloride was dissolved in 10 ml of N,N-dimethylformamide, to which 0.08 g (1.0 mmol) of dimethylamine hydrochloride and 0.22 g (2.0 mmol) of triethylamine, and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 0.28 g of N′-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoro-N,N-dimethylacetamidine (hereinafter referred to as present compound 52).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH3:14][C:4]1[CH:5]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][N:11]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:10]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCNC5)cc4C)c3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCN(S(C)(=O)=O)C5)cc4C)c3)ccc21
Reaction time: 2 h
Yield: 78.6 %

Procedure:
The crude methyl 2-((S)-6-((2′,6′-dimethyl-4′-((S)-pyrrolidin-3-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 8a (45 mg, 0.09 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of methanesulfonyl chloride (13 mg, 0.11 mmol) and triethylamine (18 mg, 0.18 mmol). The reaction solution was stirred for 2 hours. The resulting solution was added with 30 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound methyl 2-((S)-6-((2′,6′-dimethyl-4′-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 8b (40 mg, yield 77.0%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[Na].[OH-].[Na+].S(OC)(O[CH3:23])(=O)=O>O.C(O)C>[CH3:23][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COS(=O)(=O)OC
Reactant: O=S(=O)(O)c1ccc2cc(O)ccc2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2cc(S(=O)(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-hydroxynaphthalene-2-sulfonic acid, sodium salt (5 g, 20.3 mmol) in 40 mL of 2:1 H2O/ethanol is added solid NaOH (0.89 g, 22.3 mmol) at room temperature. The resulting black mixture is stirred until a homogenous solution forms, and dimethyl sulfate (2.11 mL, 22.3 mmol) is then added. The mixture is stirred over a period of 16 hours as a precipitate eventually forms. The crude mixture is concentrated in vacuo and the residue is stirred in 70 mL of absolute EtOH as a slurry. The precipitate is filtered and dried. The solid is heated at reflux in 100 mL of 95% EtOH for 2.5 hours allowed to cool to room temperature, filtered and dried to give 3.31 g of crude 6-methoxynaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (3.31 g, 12.7 mmol) in 5.3 mL of phosphorous oxychloride and phosphorous pentachloride (3.44 g, 16.5 mmol) is heated slowly to 60° C. until a homogenous solution forms and then is heated at 120° C. for 4 hours. The resulting mixture is allowed to stir at room temperature overnight, then is added slowly to a mixture of ice/ice water. The mixture is diluted with water and extracted with CHCl3. The combined organic layers are washed successively with water and saturated NaHCO3 solution. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give 4 g of a crude product. The crude product is purified by column chromatography in a gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to afford the title compound (1.51 g, 5.88 mmol) as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[CH:4][N:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cnc(Cl)nc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ncc(NC2CCOCC2)c(Cl)n1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 22.2 %

Procedure:
In a 100 mL round bottomed flask containing 2,4-dichloropyrimidin-5-amine (1.0 g, 6.10 mmol) in 16.5 mL of dichloromethane was added dihydro-2H-pyran-4 (3H)-one (0.794 g, 7.93 mmol), cooled to 0° C. then added the solution of titanium tetrachloride (0.740 ml, 6.71 mmol) in 10 mL of dichloromethane. The reaction was removed from the ice bath and with continued stirring, slowly warmed to room temperature. After 3.5 h, sodium cyanoborohydride (1.15 g, 18.29 mmol) was added in 4 equal portions over 10 minutes and the reaction was stirred at room temperature for 16 h. The suspension was diluted with water (150 mL) and transferred to an appropriate separatory funnel. The layers were separated and then extracted the aqueous layer with MTBE (1×150 mL). The organic layers were combined, washed with sat. NaCl, dried over Na2SO4, filtered and concentrated in vacuo affording a clear orange oil. The crude oil was purified by silica chromatography (30% EtOAc/Hexanes); the appropriate fractions were combined and concentrated in vacuo to afford 2,4-dichloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-amine (0.336 g, 60% pure, 22% yield). MS [M+H] found 249.1.
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:16]1[N:17]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:18]2[C:23]([N:24]=1)=[C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:21]=[C:20]([C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1)[N:19]=2>CS(C)=O>[CH:39]1([CH2:38][N:17]2[C:16]([N:12]3[CH2:13][CH2:14][CH:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH2:11]3)=[N:24][C:23]3[C:18]2=[N:19][C:20]([C:31]2[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=2)=[N:21][C:22]=3[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:40][CH2:41]1
Reactant: O=S(=O)(c1ccccc1)C1CCNC1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCC(S(=O)(=O)c5ccccc5)C4)n(CC4CC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
3-(Phenylsulfonyl)pyrrolidine (110 mg, 0.52 mmol) and dimethyl sulfoxide (0.8 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (80 mg, 0.21 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give the title compound (20 mg, 17%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH:16]=[CH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCCCCCC.[OH-:27].[Na+].OO>C1COCC1.C(OCC)(=O)C>[OH:27][CH2:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1
Reactant: C=CCOC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCCCC
Product: CC(C)(C)OC(=O)N1CCC(OCCCO)CC1
Temperature: 2.5 °C

Procedure:
To a solution of N-t-butoxycarbonyl-4-allyloxypiperidine (2.95 g) in THF (15 ml) was added 9-borobicyclo[3.3.1]nonane (9-BBN, 0.5M solution in THF) (51.3 ml) under ice-cooling with stirring, and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was cooled at 0-5° C., and 3M aqueous sodium hydroxide (20.4 ml) and 30% hydrogen peroxide aqueous solution (20.4 ml) were added the reaction mixture at 0-5° C. The mixture was stirred at ambient temperature for 1 hour. To a reaction mixture was added ethyl acetate (100 ml), and the solution was washed successively with saturated aqueous sodium chloride, 1N-hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of dichloromethane and methanol (9:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(3-hydroxypropyloxy)-N-t-butoxycarbonylpiperidine (3.83 g).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:29][CH3:30])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:11][CH:10]=1.O.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:29][CH3:30])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][S:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:13][CH:14]=1
Reactant: CCN(Cc1ccccc1Cl)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(Cc1ccccc1Cl)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 95.5 %

Procedure:
Methyl 2-{[2-(4-{2-[(2-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}-benzoate was dissolved in a mixture of THF (freshly distilled)/water (2/1, 3 ml), Lithium hydroxide (0.015 g, 0.629 mmol) was added. The reaction was performed in a single node microwave oven (5 min, 150 deg). THF was removed by evaporation. Water was added (10 ml) and the basic water phase was washed with diethyl ether (2×10 ml). Addition of HCl (2 ml, 1 M, pH 1). The water phase was extracted with two portions of DCM (20 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.103 g of 2-{[2-(4-{2-[(2-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}-benzoic acid (yield 95.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:15]([CH2:18][C:19](=[O:21])[CH3:20])(=[O:17])[CH3:16].N1CCCCC1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[C:18]([C:19](=[O:21])[CH3:20])[C:15](=[O:17])[CH3:16]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)CC(C)=O
Solvent: C1CCCCC1
Solvent: C1CCNCC1
Product: COc1cc(C=C(C(C)=O)C(C)=O)cc(OC)c1OC
Reaction time: 8 h

Procedure:
3-(3,4,5-trimethoxybenzylidene)-2,4-pentanedione (hereinafter “HSS”) was prepared by the condensation of 3,4,5-trimethoxy benzaldehyde with acetyl acetone in the presence of piperidine and cyclohexane as the reaction medium at reflux temperature under continuous azeotropic water removal. The reaction takes about eight hours to complete. The reaction product was purified by crystallization with methanol. The typical yield of HSS is about 68% with a purity, as determined by GC, of 99.1%. HSS is an off-white free-flowing powder with a melting point of 83-86° C. with a λmax at 319 nm.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:13][CH:14]1[CH2:19][CH2:18][Si:17](C2CCCC[Si]2(C2C=CC=CC=2)CCC)([C:20]2[CH:25]=[CH:24]C=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:13][C@H:14]2[CH2:15][CH2:16][Si@H:17]([C@H:20]3[CH2:21][CH2:22][Si@H:17]([CH2:16][CH2:15][CH3:14])[CH2:24][CH2:25]3)[CH2:18][CH2:19]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)F)cc1
Reactant: CCC[Si]1(c2ccccc2)CCCCC1[Si]1(c2ccccc2)CCC(CBr)CC1
Product: CCC[Si@H]1CC[C@H]([Si@H]2CC[C@H](COc3ccc(OC(F)F)cc3)CC2)CC1

Procedure:
The general procedure of Example 39 was repeated using 4-difluoromethoxyphenol and 4-bromomethyl-1-phenyl-1-silacyclohexyl-1-phenyl-1-n-propyl-1-silacyclohexane, thereby obtaining the intended product.