Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:27]1[C:36](=[O:37])[C:35]2[CH:38]=[CH:39][CH:40]=[C:33]3[C:34]=2[C:29](=[CH:30][CH:31]=[CH:32]3)[C:28]1=[O:41])[CH2:24][C:25]#[CH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][CH2:23][N:27]3[C:36](=[O:37])[C:35]4[CH:38]=[CH:39][CH:40]=[C:33]5[C:34]=4[C:29](=[CH:30][CH:31]=[CH:32]5)[C:28]3=[O:41])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCCN1C(=O)c2cccc3cccc(c23)C1=O
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Product: Cc1nnc2n1-c1sc(C#CCCN3C(=O)c4cccc5cccc(c45)C3=O)cc1C(c1ccccc1Cl)=NC2

Procedure:
Coupling of 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno[3,2-f][1,2,4] triazolo[4,3-a][1,4]diazepine with 2-(3-butyn-1-yl)-1H-benz[de]isoquinoline-1,3(2H)-dione as described in Example 37 yielded after chromatography and crystallization from ethyl acetate light yellow crystals of the title compound with m.p. 175°-179° C. A higher melting crystalline modification with m.p. 227°-229° C. was also observed.
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+]=[N-].[NH2:25][C:26]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:27]=1[CH2:28][CH2:29][C@H:30]1[O:35][CH2:34][C@@H:33]([CH2:36][O:37][C:38](=[O:45])[NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])[N:32](C(OC(C)(C)C)=O)[CH2:31]1>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([C@H:8]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C@@H:4]([C:5]([NH:25][C:26]3[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:27]=3[CH2:28][CH2:29][C@H:30]3[O:35][CH2:34][C@@H:33]([CH2:36][O:37][C:38](=[O:45])[NH:39][CH2:40][C:41]([F:43])([F:44])[F:42])[NH:32][CH2:31]3)=[O:6])[NH:1][C:21]([O:20][CH3:19])=[O:22])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccc2c(c1)OCO2

Procedure:
The title compound was prepared from (2S,3S)-2-azido-3-(benzo[d][1,3]dioxol-5-yl)-3-(4-chlorophenyl)propanoic acid (Example 1010, step 1) and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=739 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]=1[O:47][CH3:48]>>[CH3:48][O:47][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]([O:45][CH3:46])=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCCOc3ccccc3)cc2)C(O)C1
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCCOc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate as a pale yellow solid; MS: 642 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1.C(COC)OC>O>[C:19]([C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(C)c1cc(-c2ccccc2N)cc(C(C)(C)C)c1O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cc(-c2ccccc2NC(=O)CCCC(=O)O)cc(C(C)(C)C)c1O

Procedure:
A solution of 1.9 g (6.4 mmole) of the known compound 2'-amino-3,5-di-tertiary-butyl-4-hydroxybiphenyl, 0.8 g (7.0 mmole) of glutaric anhydride and 50 ml of glyme was heated on a steam bath for three hours, then an additional 0.20 g of glutaric anhydride was added. The mixture was heated at reflux for six hours, then poured into water. The aqueous mixture was extracted with diethyl ether, and the ether extracts were then washed with 10% hydrochloric acid and water. The ether solution was extracted with dilute sodium carbonate solution, and the aqueous extracts were acidified to about pH 1 with 10% hydrochloric acid. An oil separated and crystallized after scratching to initiate crystal formation. Recrystallization of the residue from aqueous ethanol provided tan crystals of N-(3',5'-di-tertiary-butyl-4'-hydroxy-2-biphenylyl)-glutaramic acid, m.p. 132°-134° C. Anaylsis: Calculated for C25H33NO4 : % C, 73.0; % H, 8.1; % N, 3.4; Found: % C, 73.0; % H, 8.0; % N, 3.3.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:32]/[O:33][CH3:34])/[C:12]([NH:14][C:15]2(SC)[CH2:19][O:18][N:17]([C:20]3([C:26]([O-:28])=[O:27])[CH2:24][CH2:23][C:22](=[O:25])[O:21]3)[C:16]2=[O:29])=[O:13])[N:10]=1)=[O:4].Cl[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42](OO)=O)[CH:37]=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:32]/[O:33][CH3:34])/[C:12]([NH:14][CH:15]2[CH2:19][O:18][N:17]([C:20]3([C:26]([O:28][CH:42]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:36][CH:37]=4)=[O:27])[CH2:24][CH2:23][C:22](=[O:25])[O:21]3)[C:16]2=[O:29])=[O:13])[N:10]=1)=[O:4]
Reactant: CO/N=C(\C(=O)NC1(SC)CON(C2(C(=O)[O-])CCC(=O)O2)C1=O)c1csc(NC(=O)CCl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O)c1csc(NC(=O)CCl)n1
Reaction time: 20 h
Yield: 62.9 %

Procedure:
In 4 ml of dry methylene chloride was dissolved 210 mg of 2-{(4RS)-4-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2(methoxyimino)acetamido]-4-methylthio-3-oxo-2-isoxazolidinyl}-5-oxo-2-tetrahydrofuran carboxylate. To the solution was added 145 mg of m-chloroperbenzoic acid, and the reaction was allowed to proceed at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to a silica-gel column chromatography, eluting with ethyl acetate - n-hexane (1:1) to give 162 mg of the above-titled Compound (30a).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]([CH3:17])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1.O>C(O)(=O)C>[Br:1][CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][N:4]([CH3:3])[CH3:17])=[CH:13][CH:12]=1)=[O:16]
Reactant: CC(=O)c1ccc(OCCN(C)C)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCOc1ccc(C(=O)CBr)cc1
Temperature: 24 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
2-(Dimethylamino)ethyl chloride hydrochloride (3.49 g, 23.2 mmol, 1.1 eq.) was added to a solution of 4′-hydroxyacetophenone (3.00 g, 22.0 mmol, 1 eq.) in acetone (100 mL), followed by the addition of potassium carbonate (9.12 g, 66.0 mmol, 3 eq.). The reaction mixture was heated under reflux overnight, cooled, and filtered; and the filtrate was concentrated and water (50 mL) was added, forming a cloudy solution. Hydrochloric acid (0.1N, 20 mL) was added, and the resulting clear solution was extracted three times with ethyl acetate. The aqueous phase was made basic with aqueous sodium hydroxide, forming a cloudy mixture, which was extracted with ethyl acetate (5×50 mL), then the ethyl acetate layer dried over magnesium sulfate and the ethyl acetate evaporated to give 4′-[2-(dimethylamino)ethoxy]acetophenone (2.90 g) as a light yellow oil, with identity and purity verified by LC-MS. Bromine (1.62 g, 10.1 mmol, 1.4 eq.) was added dropwise to a solution of the 4′-[2-(dimethylamino)ethoxy]acetophenone (1.5 g, 7.24 mmol) in acetic acid (5 mL) and the reaction mixture stirred at 24° C. for 3 hours, giving a dark red solution. The reaction mixture was cooled, water (5 mL) was added, and the mixture was lyophilized overnight. The crude 2-bromo-4′-[2-(dimethylamino)ethoxy]acetophenone was purified by preparative HPLC, followed by lyophilization of the appropriate fractions, to give 2-bromo-4′-[2-(dimethylamino)ethoxy]acetophenone (0.7 g) as an off-white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][CH3:9])(=[O:7])[CH:5]=[CH2:6]>CO>[CH3:1][N:2]([CH3:3])[CH2:6][CH2:5][C:4]([O:8][CH3:9])=[O:7]
Reactant: C=CC(=O)OC
Reactant: CNC
Solvent: CO
Product: COC(=O)CCN(C)C

Procedure:
Liquid dimethylamine (500 g) is added to 1800 ml of methanol cooled to -35°. A solution of 500 g of methyl acrylate in 850 ml of methanol is then added keeping the temperature between -50° and -60°. The reaction mixture is kept at -50° to -60° for 21/2 hours and then at room temperature overnight. The solvent is removed in vacuo and the residue is distilled under reduced pressure to give methyl 3-dimethylaminopropionate b.p. 60°-70°/16 mm Hg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])S(C2C=CC=CC=2)(=O)=O)=[C:4]([CH3:19])[CH:3]=1.[Li]C(C)(C)C.[F:25][C:26]([F:36])([F:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C(O)(C(F)(F)F)=O>C1COCC1>[F:25][C:26]([F:35])([F:36])[C:27]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:18])=[C:4]([CH3:19])[CH:3]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: Cc1cc(Br)ccc1N(C)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CNc1ccc(C(O)(c2ccccc2)C(F)(F)F)cc1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.03 g (3.23 mmol) of N-(4-bromo-2-methylphenyl)-N-methyl-benzenesulfonamide in 30 ml THF at −78° C. was added dropwise 3.9 ml (6.63 mmol) of a 1.7M solution of tert-BuLi in hexanes and the resultant mixture was stirred at −78° C. for 0.5 h. To this mixture was then added 0.66 ml (4.7 mmol) of 2,2,2-trifluoroacetophenone and the mixture stirred at −78° C. for an additional 0.5 h. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride, allowed to warm to room temperature, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. 253 mg (0.61 mmol) of this material and 3 ml of TFA was heated to 50° C. for 4 hours. After this time, excess TFA was removed in vacuo, water was added and the mixture was neutralized by the addition of a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc and combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:EtOAc, 3:1) to give the title compound. 1H-NMR (CDCl3) δ 2.12 (s, 3H), 2.92 (s, 3H), 6.57 (d, J=8.5 Hz, 1H), 7.16 (s, 1H), 7.16 (brs, 1H), 7.37-7.41 (m, 3H), 7.54-7.56 (m, 2H). Mass Spectrum (CI+) m/e=296.1 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH2:16]Cl)=[O:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C[O-].[Na+]>CN(C)C=O.CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][C:12]2=[O:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)NCCCl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(N2CCNC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1600 g of 1-(p-acetamidophenyl)-3-(2-chloroethyl) urea in 7200 ml of dimethylformamide is stirred at room temperature under an atmosphere of nitrogen. To the resulting solution is added a solution of 400 g of sodium methoxide in 2000 ml of methyl alcohol (anhydrous) in a thin stream over a 90-minute period. The temperature rises during the addition. The reaction mixture is stirred for an additional 20 minutes and then heated to 70°-75° and kept at this temperature for 1 hour. The reaction mixture is then allowed to cool slowly to 32° over a period of about 3 hours with stirring; 5000 ml of ice-water is then added rapidly. Stirring at room temperature is continued for 4 hours and the mixture is allowed to stand at room temperature overnight. The solid is filtered off and washed with 3000 ml of water and air-dried for about 2 days at room temperature to give 1-(p-acetamidophenyl)-2-imidazolidinone, m.p. 270°-273°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O.CCOC(C)=O>[N+:12]([C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 48.4 %

Procedure:
To a solution of 5-(trifluoromethyl)pyridine-2-amine (1.1 g, 6.79 mmol) dissolved in sulfuric acid (20 mL) at room temperature was added nitric acid (0.475 g, 6.79 mmol). After heating to 70° C. for 1 hr, the reaction mixture was cooled to room temperature and diluted with EtOAc and ice. The organic layer was separated, washed with sat. sodium bicarbonate aq. and brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient solvent mixture (5% MeOH-DCM to 15% MeOH-DCM) to give the title compound (680 mg). LC/MS: m/z 208(M+H). 1H-NMR (500 MHz, CD3OD): δ 8.60 (d, 1H), 8.67 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][CH:15]([C:17](O)=[O:18])[CH2:14][N:13]([CH2:20][CH:21]([F:23])[F:22])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH2:29])[CH:27]=[CH2:28].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(N(CC)CC)C>CC1CCCO1>[CH2:26]([NH:29][C:17]([CH:15]1[CH2:14][N:13]([CH2:20][CH:21]([F:23])[F:22])[CH2:12][C:11]2([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:25][CH2:24]2)[O:16]1)=[O:18])[CH:27]=[CH2:28]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)O)O2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: C=CCNC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To 9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (520 mg, 1.43 mmol), prop-2-en-1-amine (118 μL, 1.57 mmol) and T3P (2.12 mL of 50% w/w, 3.59 mmol) in 2-methyltetrahydrofuran (4 mL) was added triethylamine (597 μL, 4.28 mmol) at room temperature and the reaction mixture was stirred for 2 hours. The reaction mixture was then quenched with saturated NaHCO3 solution (3 mL) and stirred for an additional 10 minutes, then diluted with EtOAc and the layers were separated. The aqueous layer was extracted once more with EtOAc, and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to an oil. The residue was purified by silica gel column chromatography using 0-50% EtOAc in hexanes to yield tert-butyl 2-(allylcarbamoyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (480 mg, 83%). ESI-MS m/z calc. 403.2. found 404.5 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])C.O.C(=O)(O)[O-].[Na+]>C(O)=O>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:8]([N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:21]=[O:23])=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCOC(=O)c1ccc(N(C=O)Cc2ccc(Cl)cc2)cc1
Temperature: 55 °C
Yield: 67 %

Procedure:
Ethyl 4-(4-chlorobenzylamino)-benzoate (7.2 g; 0.025 mole) was dissolved in formic acid (80%; 70 ml) and the solution was heated to 55° C. with stirring. Acetic anhydride (25 ml) was added dropwise at this temperature, allowed to cool to room temperature and stirred for 1 hour. The reaction mixture was added to iced water (100 ml) and the aqueous mixture was neutralised with solid sodium bicarbonate. The product was extracted into dichloromethane (2×100 ml), washed with water (1×100 ml), dried (anhydrous MgSO4) and evaporated. Pure N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-formamide (5.32 g; 67%) was obtained by chromatography on silica-gel in dichloromethane followed by crystallisation from ethanol. M.p. 72°-3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 145 °C
Yield: 97.4 %

Procedure:
A mixture of 4-chloro-3-(trifluoromethyl)phenol (2 g, 10.18 mmol), 1-(4-fluorophenyl) ethanone (1.406 g) and K2CO3 (2.3 g, 16.64 mmol) in DMF (18 mL) was heated with a microwave condition at 145° C. for 4 h. The solution was diluted with EA and washed with water twice, dried over Na2SO4 and concentrated in vacuo to afford the title compound (3.12 g, 97% yield) as a brown oil. LCMS: rt=3.83 min, [M+H+]=315
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17][N:16]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:10][CH:9]=1.[C:40](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:40][N:3]1[N:2]=[N:1][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:23]=4)[CH2:18][CH2:17][N:16]3[C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:10][CH:9]=2)=[N:4]1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(/C=C/c3nn[nH]n3)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(/C=C/c2ccc(CC3c4ccc(OCc5ccccc5)cc4CCN3c3ccc(F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.6 %

Procedure:
To a solution containing 1-{[4-((1E)-2-(2H-1,2,3,4,-tetrazol-5-yl)vinyl)phenyl]methyl}-2-(4-fluorophenyl)-6-(phenylmethoxy)-1,2,3,4,-tetrahydroisoquinoline (430 mg, 0.831 mmol) in dimethyl formamide (12 mL) was added cesium carbonate (812 mg, 2.493 mmol) and methyl iodide (0.06 mL, 1.0 mmol). The mixture was allowed to stir at ambient temperature for 18 hours. The solvent was removed and the resulting oil was extracted with ethyl acetate and distilled water. The organic layer was dried over sodium sulfate, filtered and concentrated to afford a brown oil. The brown oil was purified by column chromatography (SiO2, 30% ethyl acetate/hexanes), to afford the title compound (100 mg, 23% yield): ES-MS (m/z) 532 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:30](=[O:31])[CH:29]=[CH:28][C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:33])([F:34])[F:20])=[CH:27][CH:26]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)C=Cc4ccc(C(F)(F)F)cc4)ccc3o2)C1
Yield: 56.7 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.040 g, 0.154 mmol), 3-(4-trifluoromethyl-phenyl)-acrylic acid (0.050 g, 0.230 mmol), HATU (0.058 g, 0.154 mmol), polystyrene-bound diisopropylamine (0.385 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (20 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Subject the mixture to flash column chromatography (12 g column, eluting with 10% 2M NH3 in MeOH/CH2Cl2) to yield the product as a yellow-white solid (0.040 g, 57%). mass spectrum (m/e): 459.0 (M+1), 457.0 (M−1). 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J=15.2 Hz, 1H), 7.61 (m, 4H), 7.53 (d, J=12.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 6.64 (d, J=15.6 Hz, 1H), 3.62-3.49 (m, 2H), 3.20 (s, 3H), 2.77-2.55 (m, 4H), 2.44-2.37 (m, 1H), 2.38 (s, 3H), 2.09-1.98 (m, 1H), 1.63-1.53 (m, 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]/[C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]/[C:60]([CH3:70])([O:62][Si:63]([CH2:66][CH3:67])([CH2:68][CH3:69])[CH2:64][CH3:65])[CH3:61])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C/CBr
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C/CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 104.1 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (E)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (116 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (85.9 mg, 99%).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[ClH:10].[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.CCCCCCC>CO>[ClH:10].[NH2:9][C:8]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=2)[N:18]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Solvent: CCCCCCC
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
A solution of pivaloylacetonitrile (750 g, 6.0 mol) and p-tolylhydrazine hydrochloride (660 g, 4.2 mol) in methanol (2.8 L) was refluxed for 3 h. Heptane was added, and methanol was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 1.05 kg, 94%. 1H NMR δ(CDCl3) 7.50 (d, 2H), 7.30 (d, 2H), 5.60 (s, 1H), 2.45 (s, 3H), 1.40 (s, 9H). MS (CI) m/z 229 (M++H).