Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH:28]([N:31]([CH:35]([CH3:37])[CH3:36])[CH2:32][CH2:33]O)([CH3:30])[CH3:29].O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:33][CH2:32][N:31]([CH:35]([CH3:37])[CH3:36])[CH:28]([CH3:30])[CH3:29])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)N(CCO)C(C)C
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OCCN(C(C)C)C(C)C

Procedure:
2-Diisopropylaminoethyl Tributylstannyl Ether is prepared from 89.4 gm (0.15 mole) bis(tributyltin) oxide and 43.5 gm (0.30 mole) 2-diisopropylaminoethanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After refluxing for 23 hours a total of 2.6 ml of water (theory 2.7 ml) had collected in the Dean-Starke tube. Solvent is stripped off on a rotating evaporator to provide 134.3 gm of orange liquid. This is fractionated at reduced pressure with collection at 147°-155° C. at 0.4 mm of 87.6 gm of straw liquid (Percent theory - 73). Infrared spectral analysis shows this liquid to be the desired ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl>CCOCC.C(Cl)Cl>[ClH:33].[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][N:37]3[CH2:36][CH2:35][O:34][CH2:39][CH2:38]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCOCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 g. (10.1 mm.) of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, 2.10 g. (10.1 mm.) of γ-morpholino-butyric acid hydrochloride and 2.18 g. (10.6 mm.) of dicyclohexylcarbodiimide are added to 200 ml. of methylene chloride. The reaction mixture is stirred at room temperature for 16 hours and after cooling, the by-product of dicyclohexylurea is removed by suction filtration. The mother liquor is evaporated to give a residue, which, after the usual workup, is converted to a dihydrochloride by the addition of an ether solution of hydrogen chloride. Recrystallization from methylene chloride/diethyl ether gives the final product.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CO)OC3=O)cc2F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A solution of 2.88 g (7.28 mmol) of the alcohol 2 in 32 mL dichloromethane at 0° C. was treated with 1.29 g (1.77 mL, 12.7 mmol) of triethylamine followed by addition of 1.04 g (0.70 mL, 9.10 mmol) of methanesulfonylchloride. The solution was stirred at 0° C. for 15 min, followed by dilution with dichloromethane and extraction with water. The solution was dried (Na2SO4) and concentrated in vacuo to afford 3.4 g (98%) of the mesylate 3 as a light pink solid (high resolution mass spectrum: calcd for C20H28FN3O7S: 473.1632. found: 473.1631), sufficiently pure for use in the next step.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH:43]1([NH:42][CH2:40][CH2:39][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: O=C(CCl)NC1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCNC3CCCCC3)cc2)c1
Yield: 6.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-cyclohexylacetamide (17 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (0.8 mg) was obtained.
Reaction SMILES: [CH2:1]([O:15][C:16]1[C:17]2[C:25]([CH:26]=[C:27]3[CH:31]=[CH:30][S:29][C:28]=13)=[C:24]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:20]1[S:21][CH:22]=[CH:23][C:19]=1[CH:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])CCC.[CH3:52][Sn:53](Cl)([CH3:55])[CH3:54].O>C1COCC1>[CH3:52][Sn:53]([CH3:55])([CH3:54])[C:22]1[S:21][C:20]2[C:24]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:25]3[C:17](=[CH:18][C:19]=2[CH:23]=1)[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:28]1[S:29][C:30]([Sn:53]([CH3:55])([CH3:54])[CH3:52])=[CH:31][C:27]1=[CH:26]3
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCCCCOc1c2cc3ccsc3c(OCCCCCCCCCCCCCC)c2cc2ccsc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1c2cc3cc([Sn](C)(C)C)sc3c(OCCCCCCCCCCCCCC)c2cc2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Compound (4b) (0.500 g, 0.752 mmol) was solubilized in anhydrous THF (40 mL) and cooled at −78° C. under N2. n-Butyllithium (0.75 mL, 2.5M) was then added and the stirring was continued for 30 minutes at this temperature and then 30 minutes at room temperature. The reaction mixture was cooled to −78° C. again before adding trimethylstannyl chloride (1.9 mL, 1.0M). The reaction was warmed up to room temperature and stirred overnight. The reaction was stopped by adding water, and the mixture was extracted with diethyl ether, dried over MgSO4, filtered, and concentrated in vacuo. The crude monomer was solubilized in 5 mL of THF and then dropped in methanol (200 mL). The product was allowed to precipitate in the freezer overnight before filtering and washing with cold methanol to afford a yellow fluffy powder as the title compound (0.650 g, 86%). 1H NMR (500 MHz, CDCl3, 298 K): 8.45 (s, 2H); 7.53 (s, 2H); 4.38 (t, J=6.6 Hz, 4H); 2.01 (quintet, J=7.9 Hz, 4H); 1.65 (quintet, J=7.7 Hz, 4H); 1.39 (m, 40H); 0.89 (t, J=7.0 Hz 6H); 0.47 (s, 18H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): 149.07; 142.85; 141.22; 132.66; 130.48; 124.58; 109.85; 73.20; 31.96; 30.65; 29.76; 29.73; 29.70; 29.57; 29.41; 26.17; 22.73; 14.17; 8.38 ppm. HRMS (ESI-TOF-MS): m/z calcd for C48H80O2S2Sn2 990.3638, found 990.3670.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16]([NH:18][S:19]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])(=[O:21])=[O:20])=[O:17])[N:9]=1.[H][H].[CH3:32]OS(OC)(=O)=O>CN(C)C=O.O>[CH3:3][O:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16]([N:18]([CH3:32])[S:19]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])(=[O:21])=[O:20])=[O:17])[N:9]=1
Reactant: COS(=O)(=O)OC
Reactant: [H][H]
Reactant: COCCSc1cc(C)nc(NC(=O)NS(=O)(=O)c2cc(Cl)ccc2Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCSc1cc(C)nc(NC(=O)N(C)S(=O)(=O)c2cc(Cl)ccc2Cl)n1
Reaction time: 12 h

Procedure:
An equivalent amount of sodium hydride (50% mineral oil dispersion) is added to a solution of N-[[4-(2-methoxyethylthio)-6-methylpyrimidin-2-yl]aminocarbonyl]-2,5-dichlorobenzenesulfonamide in dimethylformamide under a nitrogen atmosphere. After hydrogen evolution ceases, an equivalent amount of dimethylsulfate is added. After stirring for 12 hours the reaction mixture is poured into a large volume of water. The resulting precipitate is filtered to yield N-[[4-(2-methoxyethylthio)-6-methylpyrimidin-2-yl]aminocarbonyl]-2,5-dichloro-N-methylbenzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.ClC(OCC)=O.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH:24]1[O:34][CH3:35].C([N:38](CC)CC)C>ClC(Cl)Cl>[NH2:38][C:12]1[C:6]2[CH2:7][C:8]([CH3:10])([CH3:11])[O:9][C:5]=2[C:4]([C:13]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@H:24]2[O:34][CH3:35])=[O:15])=[CH:3][C:2]=1[Cl:1]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2O1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)c3c2OC(C)(C)C3)[C@H](OC)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 8.1 parts of 4-amino, 5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid in 218 parts of trichloromethane and 3.43 parts of N,N-diethylethanamine were added dropwise 3.63 parts of ethyl chloroformate, keeping the temperature below 10° C. After stirring for 1/2 hour at 10° C., the whole was added to a solution of 6.26 parts of ethyl 4-amino-3-methoxy-1-piperidinecarboxylate in 145 parts of trichloromethane at 10° C. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was washed with Water, NaOH 5% and water and was then dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 12.3 parts (93.2%) of ethyl cis-4-[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonylamino]-3-methoxy-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Cl:20][C:21]1[S:25][C:24]([NH2:26])=[C:23]([C:27]2[NH:31][CH:30]=[N:29][N:28]=2)[CH:22]=1>>[Cl:20][C:21]1[S:25][C:24]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:15])([F:13])[F:14])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])=[C:23]([C:27]2[NH:28][N:29]=[CH:30][N:31]=2)[CH:22]=1
Reactant: Nc1sc(Cl)cc1-c1nnc[nH]1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1sc(Cl)cc1-c1ncn[nH]1

Procedure:
The title compound was synthesized from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid and 5-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine according to protocol A. Retention time (min)=6.178, method [7], MS (ESI) 454.1 (M+H).); 1H NMR (300 MHz, CD3C1) δ 11.93 (b s, 1H), 8.0 (s, 1H), 7.92-7.86 (m, 2H), 7.84-7.81 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.17 (s, 1H), 6.97 (d, J=9.34 Hz, 1H), 5.30 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)=[N:4][N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)[CH2:27][CH2:26]1>>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([CH2:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:33]=4)[CH2:29][CH2:30]3)=[N:3][N:4]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc2c(-c3ccc(OC)c(OC)c3)nnc(Cl)c2c1
Product: COc1ccc2c(-c3ccc(OC)c(OC)c3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-(3,4-dimethoxyphenyl)-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [CH2:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH2:14]([Li])[CH2:15]CC.C(Br)C>C1COCC1.CCCCCC>[CH2:14]([CH:12]1[C:13]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:15]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)CC1=C2CCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCBr
Product: CCC1C2=C(CCCC2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 75 %

Procedure:
5.3 g (31.1 mmol) of the above-obtained 1,2,3,4-tetrahydrofluorene was placed in a 500 mL four-neck flask, to which 100 mL of THF was added under a nitrogen atmosphere. 10 mL (2.6 mol/L) of a hexane solution of n-butyllithium was slowly added dropwise to the solution under stirring at −78° C., followed by stirring at room temperature for 2 hours. 0.89 g (8.2 mmol) of ethyl bromide was added thereto at 0° C. over 2 minutes, followed by stirring at room temperature for 4 hours. After completing the reaction, THF was removed to provide 3.4 g of 9-ethyl-1,2,3,4-tetrahydrofluorene (9-Et-4HFluH) as a colorless oily matter (yield: 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:15][C:14]=2[CH3:30])[C:11]#[N:12])[CH:5]=[C:6]([F:8])[CH:7]=1.CSC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:15][C:14]=2[CH3:30])[CH2:11][NH2:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COCCCc1ccccc1-c1ccc(C(C#N)Cc2cc(F)cc(F)c2)c(C)c1
Solvent: CSC
Solvent: C1CCOC1
Product: COCCCc1ccccc1-c1ccc(C(CN)Cc2cc(F)cc(F)c2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(3,5-difluorophenyl)-2-[2′-(3-methoxypropyl)-3-methylbiphenyl-4-yl]propanenitrile from step 3 (1 eq.) in THF (0.1M) was added borane-dimethyl sulfide complex (5 eq.). The mixture was refluxed for 5 h without a condensor to release the dimethylsulfide. The final concentration was 0.2M. The mixture was cooled to room temperature, quenched slowly with HCl (1N). The pH was set to 10 using NaOH (1N) and finally the mixture was extracted with CH2Cl2. The organic extract was dried over Na2SO4 filtered and concentrated. Purification by column chromatography on silica gel eluting with CH2Cl2/MeOH(NH3; 2M) 5% afforded the desired compound as a colorless oil. 1H NMR (500 MHz, CD3OD): δ 7.42 (d, 1H), 7.30-7.26 (m, 2H), 7.23-7.20 (m, 2H), 7.12 (d, 1H), 7.04 (s, 1H), 6.76-6.72 (m, 1H), 6.66-6.63 (m, 2H), 3.53-3.50 (m, 1H), 3.25-3.20 (m, 7H), 3.15 (dd, 1H), 2.88 (dd, 1H), 2.65 (d, 1H), 2.64 (d, 1H), 2.12 (s, 3H), 1.70-1.65 (m, 2H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Yield: 94.3 %

Procedure:
A mixture of 33.0 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine, 74.9 g of ethyl chlorocarbonate and 170 ml of toluene was refluxed for 3.5 hrs. After cooling, the reaction mixture was washed with hydrochloric acid and water, and then dried and concentrated. The residue was solidified by treatment with n-hexane to give 37.4 g of pale yellow crystals, which were recrystallized from ethanol to give slightly yellow needles, mp 123°-124° C.
Reaction SMILES: [Na].[N+]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7](COCC[Si](C)(C)C)[N:6]=1)([O-])=O.[CH3:21][OH:22]>>[CH3:21][O:22][C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[NH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1nc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Product: COc1cc([N+](=O)[O-])[nH]n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred solution of anhydrous MeOH (25 mL) was added sodium (300 mg, 13.04 mmol) portionwise. To the clear solution was added SEM-protected 3,5-dinitropyrazole from Step D (1 g, 3.47 mmol) and the mixture was stirred at 60° C. for 2 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-30% EtOAc/hexane to afford a single regioisomer of SEM-protected 3-methoxy-5-nitropyrazole (SEM=((2-(trimethylsilyl)ethoxy)methyl)) as a clear oil (723 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 6.23 (s, 1H), 5.41 (s, 2H), 4.02 (s, 3H), 3.70-3.65 (m, 2H), 0.96-0.91 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>O.C(O)C>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)=[O:12])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 92.2 %

Procedure:
To a solution of 0.97 g of sodium hydroxide in 9.7 ml of water was added 27.1 ml of ethanol. A solution of 2.563 g of p-methylacetophenone in 4 ml of ethanol was added dropwise to the mixture, followed by dropwise addition of a solution of 2.30 g of p-methylbenzaldehyde in 4 ml of ethanol. The resulting mixture was stirred at room temperature for 3.75 hours, and the solid matter was filtered, washed with cold water and ethanol and thoroughly desiccated to give 4.16 g of 4,4'-dimethylchalcone.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][C:24]4(C)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:31])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH3:32][C:33]1([CH:38]=O)[O:37][CH2:36][CH2:35][O:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[Cl:31][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:32][C:33]3([CH3:38])[O:37][CH2:36][CH2:35][O:34]3)[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: CC1(C=O)OCCO1
Reactant: CC1(CNc2nc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)ccc2F)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(CN[C@H]2CC[C@H](Nc3cc(-c4ccc(F)c(NCC5CCOCC5)n4)c(Cl)cn3)CC2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N2′-(trans-4-aminocyclohexyl)-5′-chloro-5-fluoro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (21 mg, 0.048 mmol) in DCM (1.0 ml) was added 2-methyl-1,3-dioxolane-2-carbaldehyde (synthesized following the procedure reported in Org. Lett., 2009,11, 3542-3545), sodium triacetoxyborohydride (20.51 mg, 0.097 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC and lyophilized to give 12 mg off-white powder of the title compound as its TFA salt. LCMS (m/z): 534.1 (MH+), retention time=0.62 min.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:13]([Br:16])[C:14]#[CH:15]>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:14]1[N:3]=[N:2][N:1]([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[CH:15]=1.[Br:16][CH2:13][C:14]1[N:1]([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[N:2]=[N:3][CH:15]=1
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Reactant: C#CCBr
Solvent: Cc1ccccc1
Product: Nc1ccc(-n2cc(CBr)nn2)cc1
Product: Nc1ccc(-n2nncc2CBr)cc1
Temperature: 60 °C

Procedure:
A mixture of 1-azido-4-nitrobenzene (0.5 g, 3.0 mmol), propargyl bromide (80% in toluene) (0.7 mL, 0.6 mmol) and toluene (3 mL) in a sealed tube was heated to 60° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated to give two inseparable isomers 4-(4-(bromomethyl)-1H-1,2,3-triazol-1-yl)aniline and 4-(5-(bromomethyl)-1H-1,2,3-triazol-1-yl)aniline in a 2/1 ratio (as judged by analytical HPLC analysis) which were hydrogenated to afford a mixture of 4-(4-methyl-1H-1,2,3-triazol-1-yl)aniline and 4-(5-methyl-1H-1,2,3-triazol-1-yl)aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[O:11][CH2:10][CH2:9]2
Reactant: OCCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C2OCCc3cc(Cl)c(Cl)cc32)cc1

Procedure:
19.1 g (100 mM) of 2-(3,4-dichlorophenyl)-ethanol [G. J. Park et al.: J. Org. Chem. 22, 93 (1957)] and 15.1 g (100 mM) of 4-nitrobenzaldehyde were dissolved in 300 ml of anhydrous benzene, then 13.6 g (100 mM) of anhydrous zinc chloride were added and dry hydrochloric acid gas was led into the stirred suspension for 4 hours. Then the process described under Examples 1-7, Step a) was applied. The crude product was recrystallized from ethanol.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])C.[OH-].[Na+]>C1COCC1.CO.O>[CH2:17]([CH:5]([C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[C:4]([OH:24])=[O:3])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)NOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.7 %

Procedure:
To a solution of the 2-benzyl-N-benzyloxy-malonamic acid ethyl ester (19 g, 58.1 mmol) dissolved in a mixture of THF (70 mL) and MeOH (200 mL) was added a solution of NaOH (5.4 g, 135 mmol) in water (100 mL). The mixture was stirred at room temperature for 24 hours, and evaporated to remove volatile organic solvents. The aqueous residue was diluted with water (200 mL), and washed with DCM (200 mL). The aqueous layer was saved and acidified to pH˜4 by adding concentrated HCl. The desired product was precipitated, washed with water, dissolved in acetone (200 mL), and evaporated to dryness, affording intermediate (12a) as a white solid (14.2 g). 1H-NMR (CD3OD, 300 MHz) δ (ppm) 7.20-7.06 (m, 5H), 4.60-4.56 (d, 1H), 4.42-4.38 (d, 1H), 3.10-2.98 (m, 2H).