Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][C@@H:2]1[N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][CH:9]=[N:10][C:11]=2[NH2:15].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].C(Cl)Cl.CO.CO>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH2:3][C@@H:2]1[N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][CH:9]=[N:10][C:11]=2[NH:15][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ncnc2c1ncn2[C@H]1CC=CO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ncnc2c1ncn2[C@H]1CC=CO1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a suspension of the product of Step C (196 g, 0.97 mole), 4-dimethylaminopyridine (5.9 g, 0.048 mole) in dry pyridine (970 mL) at 26° C. was added dropwise over 1 hr trimethylacetylchloride (145 mL, 142.1 g, 1.18 mole, 1.2 equiv.). A slight 3° C. exotherm was noted. The reaction mixture was then heated to 55° C. for 4 hr becoming a pale yellow-orange solution. Analysis by TLC (methylene chloride: methanol (90:10), Rf (product) 0.75) showed the reaction was complete. The reaction solution was cooled to 25° C. and methanol (40 mL) was slowly added. The reaction solution was then stirred for 30 min, then concentrated in vacuo to a thick orange syrup. The residue was dissolved in methylene chloride (1.5 liters) and washed with 0.5N sodium bisulfate (3×500 mL), 1N sodium bisulfate (2×500 mL), then brine (1×500 mL). All aqueous washes were combined and extracted with methylene chloride (1×500 mL). All methylene chloride extracts were combined and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo light orange oil. The oil was suspended in toluene (200 mL) and concentrated in vacuo. The product solidified to a pale yellow solid weighing 262 g for a yield of 94%.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[NH:10][N:9]=[C:8]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([NH:18][CH3:19])=[O:17])[CH:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:39]=[CH:38][C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:19][NH:18][C:16]([C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:8]2[CH:7]=[C:6]([NH:5][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:39][CH:38]=3)[NH:10][N:9]=2)[CH:22]=[CH:21][CH:20]=1)=[O:17]
Reactant: CNC(=O)c1cccc(CCc2cc(N)[nH]n2)c1
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CNC(=O)c1cccc(CCc2cc(NC(=O)c3ccc(N4CCN(C)CC4)cc3)[nH]n2)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 32.5 %

Procedure:
A 2M solution of trimethylaluminium (0.936 mL, 1.87 mmol) in toluene, was added drop-wise to a stirred suspension of 3-(2-(5-amino-1H-pyrazol-3-yl)ethyl)-N-methylbenzamide (0.183 g, 0.75 mmol) and methyl 4-(4-methylpiperazin-1-yl)benzoate (0.176 g, 0.75 mmol) in toluene (5 mL) at room temperature. The solution was then stirred at 60° C. for 18 h. The reaction mixture was cooled, poured into methanol (5 ml) and acidified with 2N HCl (15 ml). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford an oil. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.109 g, 32.6%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[BH4-].[Na+]>CO.ClCCl>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([OH:14])[CH3:13])[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
To a stirred solution of 3α-hydroxy-5α-pregnan-20-one (3.2g, 318.5 g/m, 10 mmol) in 160 mL of methanol and 30 mL of dichloromethane at room temperature was slowly added sodium borohydride (3.3 g, 37.8 g/m, 87 mmol) over a period of 2 h. The mixture was stirred for an additional hour and then poured into ice cold water (700 mL) and extracted three times with ether. The combined organic phase was washed several times with water, dried over magnesium sulfate and concentrated to a white solid (2.35 g, 320.5 g/m, 7.3 mmol, 73%).
Reaction SMILES: [C:1](=[O:11])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:2][CH3:3].[C:12]1(O)[CH:17]=[CH:16]C=[CH:14][CH:13]=1.C(=O)(OC)OC>CO>[C:1](=[O:11])([O:2][C:3]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)Oc1ccccc1
Solvent: CO
Solvent: COC(=O)OC
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
In a column apparatus as described in Example 15, in which, instead of the 10-tray sieve-plate column, a 10-tray bubble-cap tray column, isothermically thermostatted to 183° C., of length 72 cm and internal diameter 4.75 cm was used, there was reacted, under the conditions described there, a mixture of 150 g/h of methyl phenyl carbonate, 350 g/h of phenol and 6.25 g/h of octylstannonic acid. After establishment of constant conditions, at the head of the apparatus, 365 g/h of a mixture of 1.3% by weight of methanol, 8.5% by weight of dimethyl carbonate and 90.2% by weight of phenol was continuously withdrawn and, at the foot of the column, 135 g/h of a mixture of 6.2% by weight of phenol, 14.0% by weight of methyl phenyl carbonate and 79.8% by weight of diphenyl carbonate were continuously withdrawn. This represents a space-time yield for the formation of diphenyl carbonate of 0.085 g·ml-1· h-1, based on the reactor volume. 16.6% of the methyl phenyl carbonate used reacted with phenol with transesterification to form diphenyl carbonate. The selectivity of the formation of diphenyl carbonate was >99%, that is no by-products could be detected.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:13])=O.CN(C)C=O>ClCCl>[Cl:13][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1nccc(CO)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nccc(CCl)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 13.69 g of [2-(methylthio)pyrimidin-4-yl]methanol obtained in stage a) in 250 mL of dichloromethane are added dropwise 7.67 mL of thionyl chloride, followed by 3.91 mL of N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue is taken up in diisopropyl ether and the solid formed is filtered off and dried to give 10.28 g of 4-(chloromethyl)-2-(methylthio)pyrimidine, the characteristics of which are as follows:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[C:12]([NH2:35])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1>C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:35][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: -5 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A solution of acryloyl chloride (0.584 mL, 1M in CH2Cl2, 0.58 mmol) was added dropwise to N1-(2-dimethylaminoethyl)-N4-[4-(1H-indol-3-yl)pyrimidin-2-yl]-5-methoxy-N1-methylbenzene-1,2,4-triamine (Intermediate 168, 252 mg, 0.58 mmol) in CH2Cl2 (10 mL) and the mixture was then stirred at −5° C. for 1 h. The mixture was then diluted with CH2Cl2 (100 mL), and the resulting solution was washed with sat. NaHCO3 (25 mL), water (25 mL), and then sat. brine (25 mL), and was then concentrated in vacuo. Purification by FCC, eluting with 0-30% CH3OH in CH2Cl2 gave the title compound (76 mg, 27%) as a white solid; 1H NMR (CDCl3) 2.25 (6H, s), 2.27-2.34 (3H, m), 2.69 (3H, s), 2.84-2.94 (2H, m), 3.87 (3H, s), 5.68 (1H, dd), 6.40 (1H, d), 6.48 (1H, dd), 6.78 (1H, s), 7.03 (1H, d), 7.08-7.20 (2H, m), 7.33 (1H, dd), 7.65 (1H, s), 8.12 (1H, d), 8.26 (1H, d), 8.59 (1H, s), 9.74 (1H, s), 9.97 (1H, s), 10.24 (1H, s); m/z: ES+ MH+ 486.
Reaction SMILES: [CH2:1]([S:5]([N:8]([C@H:27]([C:29]([O:31]C(C)(C)C)=[O:30])[CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:12][CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].Cl>C(O)(=O)C>[CH2:1]([S:5]([N:8]([C@H:27]([C:29]([OH:31])=[O:30])[CH3:28])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:14][CH:15]=1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Product: CCCCS(=O)(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@@H](C)C(=O)O

Procedure:
750 mg of (S)-N-butanesulfonyl-N-(1-tert.-butoxycarbonylethyl)-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine are treated for 24 hours at 0° with a solution of hydrogen chloride in glacial acetic acid (1.9N). Evaporation of the mixture and flash-chromatography of the residue (100 g of silica gel; CH2Cl2 /ethyl acetate/toluene/formic acid=40:40:20:4) yields the (S)-N-butanesulfonyl-N-(1-carboxyethyl)-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in the form of a white amorphous powder [m.p.: 90° (decomposition at 127°)].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([NH2:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:11][C:12]1[CH:21]=[C:20]([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)c1cc(N)cc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)cc(Nc2ncccc2[N+](=O)[O-])c1
Yield: 20.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (3.20 g), methyl 3,5-diaminobenzoate (3.20 g) and potassium carbonate (4.0 g) in 1,4-dioxane (60 ml) was stirred under reflux for 4 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel column (5% methanol in chloroform) to give 2-(3-amino-5-methoxycarbonylphenylamino)-3-nitropyridine (1.12 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]([OH:29])[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[O:29]=[C:20]1[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=3)[CH2:14][CH2:15]2)=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1
Reactant: CCOC(=O)c1cc(Cl)ncn1
Reactant: OC1Nc2ccccc2C=C1C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(N2CCC(c3cc4ccccc4[nH]c3=O)CC2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
730 mg (3.91 mmol) ethyl 6-chloropyrimidine-4-carboxylate were placed in 10 mL DMF. 900 mg (3.94 mmol) 3-piperidin-4-yl-1,2-dihydro-quinolin-2-ol and 2.30 mL (13.4 mmol) DIPEA were added and the reaction mixture was stirred overnight at RT. The reaction mixture was mixed with 60 mL water and stirred for 30 min. The precipitated solid was suction filtered and dried.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[S:10][C:4]=2[CH2:3]1.FC(F)(F)C([O-])=O>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:4]=2[CH2:3]1
Reactant: COC(=O)c1cc2c(s1)CN(C)CC2
Agent: O=C([O-])C(F)(F)F
Product: CN1CCc2cc(C(=O)O)sc2C1

Procedure:
Prepared analogously to Example 45b from methyl 6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-2-carboxylate (as the trifluoroacetate salt).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.Br.BrCC1C=CC=CN=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]2)[C:21]1=[O:40].FC1C2OCCOC=2C=C2OCC3(C4C(=CC=CC=4)NC3=O)C=12>>[O:40]=[C:21]1[C:22]2([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]2)[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]1[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Product: O=C1N(Cc2cc(=O)[nH]c(=O)[nH]2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 5.25 and making non-critical variations using 6-(chloromethyl)uracil to replace 2-(bromomethyl)pyridine hydrobromide, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 6-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]pyrimidine-2,4(1H,3H)-dione was obtained (5%) as an off-white solid: mp>300° C.; 1H NMR (300 MHz, DMSO-d6) δ11.11 (s, 1H), 11.05 (s, 1H), 7.29 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=6.8 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 7.03 (dd, J=7.7, 7.7 Hz, 1H), 6.66 (s, 1H), 6.26 (s, 1H), 5.90 (s, 2H), 5.14 (s, 1H), 4.75 (ABq, 2H), 4.60 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.4, 164.2, 155.9, 151.8, 151.5, 148.8, 142.3, 142.2, 132.1, 129.4, 124.2, 123.9, 120.1, 109.8, 103.6, 101.9, 96.9, 93.8, 80.4, 57.9, 40.5; MS (ES+) m/z 406.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1cnc(Cl)cc1OC
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc(NCc2ccc(OC)cc2OC)cc1OC
Temperature: 120 °C
Reaction time: 19 h
Yield: 64.6 %

Procedure:
To a solution of methyl 6-chloro-4-methoxypyridine-3-carboxylate (1.09 g) in N,N-dimethylacetamide (12 mL), 2,4-dimethoxybenzylamine (1.35 g) and potassium carbonate (2.24 g) were added at room temperature, and the mixture was stirred at 120° C. for 19 hours. The reaction solution was cooled to room temperature, then diluted with ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: hexane/ethyl acetate) to obtain the title compound (1.16 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH:10]([CH3:21])[N:11](C(OCC)=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH:10]([CH3:21])[NH:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1C
Agent: Cl
Product: CC1NCC2CCN(Cc3ccccc3)C21

Procedure:
16 g (55 mmol) of ethyl 2-benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is concentrated, and the residue is dissolved in 50 ml of water and rendered alkaline with potassium carbonate. The mixture is extracted five times using 50 ml of chloroform each time, the extracts are dried over K2CO3 and concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](Br)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C([Li])CCC.CCCCCC>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=C(Br)c3ccccc32)CC1
Reactant: C1CCNCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCC(=C2c3ccccc3C=C(N3CCCCC3)c3ccccc32)CC1

Procedure:
1-Methyl-4-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 7.32 g. (0.02 mole) is dissolved in 100 ml. of dry piperidine. To this solution is added slowly 25 ml. of a 1.6M solution of butyl lithium in hexane (0.04 mole) under anhydrous conditions and then stirred and refluxed for 8 hours under anhydrous conditions. The reaction is cooled and poured into 500 ml. of benzene and extracted 6 times with 100 ml. of water. The benzene is dried over anhydrous MgSO4, filtered, and the benzene removed on a rotary evaporator leaving 1-methyl-4-(10-(1-piperidyl)-5H-dibenzo[a,d]-cyclohepten-5-ylidene)piperidine as an oil which still has some solvent in it.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.[NH2:21][C:22]([NH2:24])=[O:23].[H-].[Na+]>C(O)C>[F:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[C:10]1[C:11]([OH:13])=[N:21][C:22]([OH:23])=[N:24][C:16]=1[OH:18]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(O)c(-c2c(F)cc(F)cc2F)c(O)n1
Temperature: 80 °C

Procedure:
To a mixture of diethyl 2-(2,4,6-trifluorophenyl)malonate (580 mg, 2.0 mmol, U.S. Pat. No. 6,156,925) and urea (360 mg, 6.0 mmol) in 10 mL of ethyl alcohol at room temperature is added sodium hydride (60% in mineral oil, 160 mg, 4.0 mmol). The mixture is then heated at 80° C. for 3 days, cooled to room temperature, and partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer is extracted with ethyl acetate, and the combined organic extracts are dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 10% methyl alcohol in ethyl acetate. Concentration provides 5-(2,4,6-trifluorophenyl)pyrimidine-2,4,6-triol as a light tan solid (148 mg). MS: m/z 257.0 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:28]([O:32][C:33](=[O:39])[C@@H:34]([CH:36]([CH3:38])[CH3:37])[NH2:35])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:32][C:33](=[O:39])[C@@H:34]([CH:36]([CH3:37])[CH3:38])[NH:35][S:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)(=[O:15])=[O:14])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Br)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a 0° C. suspension of 4-(4-bromophenoxy)benzene sulfonyl chloride (1.10 g, 3.16 mmol) in 20 mL of dichloromethane was added a solution of diisoproylethylamine (1.10 mL, 6.3 mmol) and D-valine tert-butyl ester (660 mg, 3.8 mol) in 11 mL of dichloromethane. The ice bath was removed, and the reaction was stirred for 3 h, diluted with 30 mL dichloromethane, and 30 ml of 1 M HCl was added. The layers were separated, and the aqueous layer was washed with 30 mL of dichloromethane. The combined dichloromethane fractions were washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica, eluting with 25% ethyl acetate in hexane, to give 980 mg (64%) of N-[4-(4-bromophenoxy)benzenesulfonyl]-D-valine t-butyl ester as a white foam.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:53]=[CH:52][C:51]([S:54]([NH:57][C:58]2[CH:63]=[CH:62][C:61]([C@@H:64]3[CH2:70][C@@H:69]4[C@H:65]3[CH2:66][N:67]([CH2:71][CH2:72][CH3:73])[CH2:68]4)=[CH:60][CH:59]=2)(=[O:56])=[O:55])=[CH:50][CH:49]=1.[CH3:74][O:75][CH2:76][C@H:77]1[CH2:81][CH2:80][CH2:79][NH:78]1.ClCCl.CO>O1CCCC1>[CH3:74][O:75][CH2:76][C@H:77]1[CH2:81][CH2:80][CH2:79][N:78]1[C:48]1[CH:53]=[CH:52][C:51]([S:54]([NH:57][C:58]2[CH:63]=[CH:62][C:61]([C@@H:64]3[CH2:70][C@@H:69]4[C@H:65]3[CH2:66][N:67]([CH2:71][CH2:72][CH3:73])[CH2:68]4)=[CH:60][CH:59]=2)(=[O:56])=[O:55])=[CH:50][CH:49]=1
Reactant: COC[C@H]1CCCN1
Reactant: CCCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(Br)cc4)cc3)[C@@H]2C1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(N5CCC[C@@H]5COC)cc4)cc3)[C@@H]2C1
Reaction time: 2 h
Yield: 17.5 %

Procedure:
A solution of 0.07 g rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 0.11 mmol) and 0.043 g tri(dibenzylideneacetone)dipalladioum(0) (0.05 mmol) in 5 ml tetrahydrofuran were added dropwise to a solution of 4-bromo-N-[4-((1R,5S,6R)-3-propyl-3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-benzenesulfonamide (0.26 g, 0.59 mmol), (R)-2-(methoxymethyl)pyrrolidine (104 mg, 0.9 mmol), and 0.104 g sodium tert.butylate (1.08 mmol) in 20 ml tetrahydrofuran. The reaction mixture was refluxed for 5½ hours, and, after additional addition of 0.04 ml (R)-2-(methoxymethyl)pyrrolidine, for another 2 hours. After evaporation, the residue was treated with water, extracted twice with diethyl ether and dichloromethane each, and the combined organic layers dried over magnesium sulfate, filtered, and the solvent evaporated. Purification of the thus obtained crude product via silica gel chromatography using a gradient of dichloromethane/methanol 0-12% gave 50 mg (yield 18%) of the title compound.
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([CH3:12])[CH2:10][OH:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:46]=[CH:45][C:44](F)=[CH:43][CH:42]=3)[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>CS(C)=O>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:42]=[CH:43][C:44]([N:6]4[CH2:7][CH2:8][N:3]([CH:9]([CH3:12])[CH2:10][OH:11])[CH2:4][CH2:5]4)=[CH:45][CH:46]=3)[NH:37][N:38]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: CC(CO)N1CCNCC1
Reactant: COc1cc(CCc2cc(NC(=O)c3ccc(F)cc3)[nH]n2)cc(OC)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(C)CO)CC4)cc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.4 %

Procedure:
2-(piperazin-1-yl)propan-1-ol 2HCl (0.274 g, 1.26 mmol) was added to N-ethyl-N-propan-2-ylpropan-2-amine (0.330 mL, 1.89 mmol) in DMSO (5 mL). The reaction mixture was stirred at room temperature for 10 mins. N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamide (0.233 g, 0.63 mmol) was added and the mixture heated at 110° C. for 18 h under nitrogen. Heating was continued for 12 additional days. The reaction was cooled and the crude mixture was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.048 g, 15.44%) as a cream solid.