Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([C@H:20]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21]1)([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)C(O)=O)=[O:4].C([N:30]([CH2:33]C)CC)C.C1C=CC([O:41]P(OC2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1.O>C1(C)C=CC=CC=1>[N:30]([C:5]([C@H:20]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21]1)([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[C:33]=[O:41]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)C(Cc1cccc2ccccc12)(C(=O)O)[C@H]1C[C@@H](C(=O)OC)C1
Reactant: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1cccc2ccccc12)(N=C=O)[C@H]1C[C@@H](C(=O)OC)C1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of cis-2-methoxycarbonyl-2-(3-methoxy carbonylcyclobutyl)-3-naphthylpropanoic acid (0.25 g, 0.68 mmol), dry triethylamine (72 mg, 0.71 mmol) and diphenylphosphonic azide (0.2 g, 0.71 mmol) in dry toluene (10 ml) was heated with stirring at 80° C. under a nitrogen atmosphere for 20 hours. After cooling the reaction mixture, water was added and the organic phase separated. The aqueous phase was extracted with diethyl ither and the combined organic phases dried, filtered and evaporated to an oil. The crude product was purified by chromatography on flash silica eluting with diethyl ether-hexane (1:1) to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.N1C=CC=CC=1.O.[NH2:23][NH2:24]>O>[Br:1][C:2]1[C:3]([NH:23][NH2:24])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2ccnc(Cl)c2Br)cc1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1nccc(-c2ccc(Cl)cc2)c1Br
Temperature: 120 °C

Procedure:
A mixture of 3-bromo-2-chloro-4-(4-chlorophenyl)pyridine (10 g, 33 mmol), pyridine (50 mL) and hydrazine monohydrate (4.8 g, 96 mmol) was heated to 120° C. for 16 h. After cooling to room temperature, water (300 mL) was added, which caused solid desired product to precipitate. This was filtered, washed with water (2×50 mL), and dried to obtain the title compound as a pale yellow solid (6 g), which was used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]([C:21]#[N:22])[C:18]3[N:23]=[N:24][N:25]([CH3:26])[C:17]=3[CH:16]=2)=[CH:11][C:10]=1[C:27]([F:30])([F:29])[F:28])(=O)=O.[CH3:31][C:32]1[N:37]=[C:36]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][CH:33]=1>CN1CCCC1>[CH3:26][N:25]1[C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:41]4[CH2:42][CH2:43][N:38]([C:36]5[CH:35]=[CH:34][CH:33]=[C:32]([CH3:31])[N:37]=5)[CH2:39][CH2:40]4)=[C:10]([C:27]([F:28])([F:29])[F:30])[CH:11]=3)[N:20]=[C:19]([C:21]#[N:22])[C:18]=2[N:23]=[N:24]1
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Agent: CN1CCCC1
Product: Cc1cccc(N2CCN(CCOc3ccc(-c4cc5c(nnn5C)c(C#N)n4)cc3C(F)(F)F)CC2)n1
Temperature: 150 °C
Yield: 7.4 %

Procedure:
A mixture of 2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate (0.15 g) and 1-(6-methylpyridin-2-yl)piperazine (0.361 g) in N-methylpyrollidine (2 ml) was heated at 150° C. under microwave condition for 30 minutes. Solvent removed under vacuum and residue dissolved in methanol (1 ml) and purified by basic prep HPLC to give methyl-6-(4-(2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.0132 g). 1H NMR (MeOD) δ: 8.45 (m, 3H), 7.43 (m, 2H), 6.57 (m, 2H), 4.46 (s, 3H), 4.41 (m, 2H), 3.35 (m, 3.35), 2.97 (m, 2H), 2.78 (m, 4H), 2.35 (s, 3H). MS m/z 523.2 (M+H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH2:47]I>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:47][C:46]2[CH:49]=[C:50]([O:54][CH3:55])[C:51]([O:52][CH3:53])=[C:44]([O:43][CH3:42])[CH:45]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: COc1cc(CI)cc(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1cc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc(OC)c1OC

Procedure:
In analogy with Example 44c), 1 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 2b)] in 4 ml of abs. THF is deprotonated (-75° C.) with 6.42 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and with the addition of 0.66 ml of DMPU and alkylated with 1.008 g 3,4,5-trimethoxybenzyl iodide. Chromatography on silica gel (eluent, hexane/acetone 3:1) affords the title compound. TLC Rf (hexane/acetone, 3:1)=0.22. FAB-MS M+ =485.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28](Br)[C:27](=[O:32])[N:26]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:51]([O:53][CH2:54][CH3:55])=[CH2:52])CCC>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28]([C:51]([O:53][CH2:54][CH3:55])=[CH2:52])[C:27](=[O:32])[N:26]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)ncc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 104.6 %

Procedure:
A 6-dram vial was charged with {1-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (379 mg, 0.65 mmol) and tetrakis(triphenylphosphine) palladium(0) (75 mg, 0.065 mmol) and the atmosphere replaced with argon. Toluene (5 ml) was added followed by tributyl-(1-ethoxy-vinyl)-stannane (352 mg, 0.97 mmol). The vial was heated to 110° C. and stirred for 12 h. The reaction mixture was diluted with chloroform (25 ml) and adsorbed onto silica gel. Chromatographic purification on silica gel (chloroform/2-propanol+1% TEA gradient) gave (1-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester as a yellow solid (394 mg, 0.68 mmol). MS: (APCI+) 576 (M+1, 100), 548.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH:6]2[CH:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[C:11]([CH3:12])=[C:5]2[O:4]1.[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[OH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH:6]2[CH:8]([CH3:14])[C:9]([N+:16]([O-:18])=[O:17])=[C:10]([CH3:13])[C:11]([CH3:12])=[C:5]2[O:4]1
Reactant: O=[N+]([O-])O
Reactant: CC1=CC(C)C2CC(C)(CO)OC2=C1C
Solvent: CC(=O)O
Product: CC1=C2OC(C)(CO)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 0 °C

Procedure:
2.3 g of 2-hydroxymethyl-2,4,6,7-tetramethyldihydrobenzofuran was dissolved in 30 ml of anhydrous acetic acid and 1.9 ml of nitric acid was added dropwise while stirring at 0° C. After stirring at 0° C. for one hour, the solution was poured into ice-water, followed by stirring at room temperature for one hour. The reaction solution was extracted with ether, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform) to obtain 1.34 g of the objective product.
Reaction SMILES: [Cl:1]C1C=CC2N(C)C(=O)[CH2:9][N:8]3C=NN=[C:7]3[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:28]([CH3:29])[C:27](=[O:30])[CH2:26][N:25]3[C:31](C(F)(F)F)=[N:32][N:33]=[C:24]3[C:23]=2[CH:38]=1>>[ClH:1].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:28][CH3:29])=[C:23]([C:24]2[N:25]([CH2:26][C:27](=[O:30])[N:8]3[CH2:7][CH2:6][CH2:17][CH2:9]3)[CH:31]=[N:32][N:33]=2)[CH:38]=1
Reactant: CN1C(=O)Cn2cnnc2-c2cc(Cl)ccc21
Reactant: CN1C(=O)Cn2c(nnc2C(F)(F)F)-c2cc(Cl)ccc21
Product: CNc1ccc(Cl)cc1-c1nncn1CC(=O)N1CCCC1
Product: Cl

Procedure:
Following the procedure of example 1b but substituting an equivalent amount of 10-chloro-7-methyl-5H-s-triazolo[4,3-d]-[1,4]benzodiazepin-6(7H)-one for the 10-chloro-7-methyl-3-(trifluoromethyl)-5H-s-triazolo[4,3-d][1,4]benzodiazepin-6(7H)-one, one obtains the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][C:17]=2[Cl:19])=[CH:6][CH:5]=1)=[O:11]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
4-Bromo-benzoic acid methyl ester (3 g) was dissolved in a mixture of toluene (20 mL) and ethanol (20 mL). 2,4-Dichloro-phenyl boronic acid (3 g) was added followed by 2 M Na2CO3 (20 mL). The mixture was stirred vigorously under N2 and (PPh3)4Pd (0.5 g) added. The mixture was refluxed with stirring for 3 hours under an atmosphere of N2. The solvent was removed under vacuum, the residue was dissolved in ethyl acetate, and washed with water and saturated NaCl solution. After drying (Na2SO4), the solvent was evaporated and the resultant oil purified by column chromatography to give a fluffy white powder, which was recrystallised from ethanol to give the title compound as long needles. 13C NMR (CDCl3): δ 52.3, 127.3, 129.5, 129.5, 129.6, 129.9, 131.9, 133.1, 134.4, 138.1, 142.8 and 166.8. 1H NMR (CDCl3): δ 3.93 (3H, s), 7.27 (2H, m), 7.47 (2H, d, J=8.5 Hz), 7.49 (1H, s) and 8.09 (2H, d, J=8.2 Hz).
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:32][O:31][C:29]1[CH:28]=[C:26]([N:27]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:11](=[O:21])[C:2]([CH3:1])=[C:3]2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:30]=1
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: COc1cc(N)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: COc1cc(OC)cc(-n2c(-c3ccccc3)cc(=O)c(C)c2-c2ccccc2)c1

Procedure:
To 170 ml of chlorobenzene were added 4.2 g (0.015 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 11.5 g (0.075 mole) of 3,5-dimethoxyaniline, 5.2 g (0.027 mole) of para-toluenesulfonic acid and 35.0 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 2 hours. After cooling the reaction mixture, solid matter was removed from the reaction mixture, followed by addition of 200 ml of chloroform thereto. The organic layer was washed first with 200 ml of 10% hydrochloric acid and then with 200 ml of a 10% aqueous solution of sodium hydroxide. The organic layer was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate by filtration, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from a 2:1 mixed solvent of acetone and hexane, 2.0 g of 1-(3,5-dimethoxyphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 232°-236° C. was obtained.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:20]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:15][CH2:14][CH2:13][O:12][C:8]2[CH:7]=[C:6]([CH2:5][CH:4]([O:17][CH3:18])[C:3]([OH:2])=[O:19])[CH:11]=[CH:10][CH:9]=2)[CH:21]=1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2cccc(-c3ccccc3)c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and biphenyl-3-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C25H26O5 [M+Na]+: 429.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10](O)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=C=O)=[CH:19][CH:18]=1>C(N(CC)CC)C.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cc(Br)co1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC(Nc1ccc(Cl)cc1)C(Cl)(Cl)Cl)c1cc(Br)co1

Procedure:
was prepared in accordance with reported methods: see Ulrich, H. et al J Org. Chem., 33, 1968, 2887. A solution of 4-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide (preparation as for 6 above) (0.566 g, 1.67 mmol), 1-chloro-4-isocyanato-benzene (0.264 g, 1.68 mmol) and triethylamine (2 drops) in benzene (4 mL) was heated at 95° C. for 1.5 h. The mixture was evaporated under reduced pressure. The residue was solvated with chloroform and concentrated onto silica gel. Chromatographic purification on an auto-column with 30% dichloromethane in hexanes gave 4-bromo-N-(2,2,2-trichloro-1-(4-chlorophenylamino)ethyl)furan-2-carboxamide (Compound 33) as a white solid; 422 mg (57%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2(N)[CH2:18][CH2:17]2)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([O:23]C(=O)C)(=O)[CH3:21].CO.[N:29]1C=CC=CC=1>CN(C)C1C=CN=CC=1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH2:21][C:20]([NH2:29])=[O:23])[CH2:18][CH2:17]2)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C2(N)CC2)nc1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C2(CC(N)=O)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[5-(tert-Butyldimethylsilanyloxymethyl)pyridin-2-yl]cyclopropylamine (190 mg) was dissolved in pyridine (2 ml), acetic anhydride (0.13 ml) and 4-dimethylaminopyridine (17 mg) were added, and the mixture was stirred at room temperature for 4 hr. Methanol (2 ml) was added and the mixture was stirred for about 10 min. The solvent was evaporated, and the residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size L, elution solvent: hexane/ethyl acetate) to give the title compound (158 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH3:31][C:26]1[CH:25]=[CH:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:22]=2)[N:27]=1
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution- of 0.4n-propylbenzenesulphonyl chloride (145 mg, 0.664 mmol) in dichloromethane (4 mL) was added pyridine (130 μL, 1.58 mmol) and the mixture was stirred- under N2 for 5 min, after which time 6-amino-2-methylquinoline (100 mg, 0.632 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (186 mg, 86%), single spot at Rf 0.70 (ethyl acetate). mp 173.7-174.0° C., HPLC purity 99+% (tR 2.32 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.94 (1H, d, J=8.4 Hz), 7.89 (1H, d, J=9.2 Hz), 7.67 (2H, d, J=8.4 Hz), 7.54 (1H, d, J=2.5 Hz), 7.31 (1H, dd, J=8.9, 2.5 Hz), 7.25 (1H, d, J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz), 7.07 (1H, s, N—H), 2.70 (3H, s), 2.56 (2H, t, J=7.5 Hz), 1.58 (2H, sextet, J=7.4 Hz), 0.87 (3H, t, J=7.4 Hz). LCMS: 339.24 (M−). FAB-MS (MH+, C19H20N2O2S): calcd 341.1323, found 341.1324.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]1([Mg]Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(Br)CCCCC1.[Mg].C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[OH:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Br[Mg]C1CCCCC1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: BrC1CCCCC1
Solvent: C1CCOC1
Product: Oc1ccc(Br)cc1C(O)C1CCCCC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 147 %

Procedure:
A solution of 3.35 g (0.0167 mole) 5-bromo-2-hydroxybenzaldehyde in 15 ml dry tetrahydrofuran (HF) was cooled to -78° C. To this was added dropwise over seven minutes, a solution of 9.37 g (0.050 mole) cyclohexylmagnesium bromide (prepared by reaction of cyclohexylbromide with an equimolar amount of magnesium turnings in THF under anhydrous conditions) in THF (50 ml). The reaction mixture was stirred at -78° C. for 1.5 hours, then at -10° C. for another hour. The reaction was quenched by addition of 3.0 g (0.050 mole) acetic acid, the mixture allowed to warm slowly to room temperature and stirred for 70 hours. Evaporation of solvent gave a viscous oil which was partitioned between 500 ml ethyl acetate and 300 ml 1N hydrochloric acid. The organic layer was washed with saturated sodium bicarbonate (2×300 ml), brine, dried (MgSO4), filtered and solvent evaporated in vacuo to yield 7.0 g of product as a viscous oil. The oil was purified by silica gel chromatography, eluting with 4:1 hexane/ethyl acetate to obtain 3.7 g (78%) of product which crystallized upon standing, m.p. 110-113° C. M.S. m/e): 286, 284, 268, 266, 201 (base).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[CH2:10]1[CH:15]2[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]2[CH2:13][CH2:12][N:11]1[CH2:29][CH2:30][CH2:31][OH:32].C(OCC)(=O)C>C(Cl)Cl>[C:3](=[O:4])([O:32][CH2:31][CH2:30][CH2:29][N:11]1[CH2:12][CH2:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][C:17]3[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=3[CH:15]2[CH2:10]1)[NH2:5]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: OCCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)OCCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
0.2 ml of trichloroacetyl isocyanate were added to a solution of 400 mg of 3-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)propanol (prepared as described in Example 16) in 20 ml of methylene chloride, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in 22 ml of methanol, 9.0 g of silica gel were added to the solution and the mixture was stirred at room temperature for 15 hours. At the end of this time, the mixture was filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel eluted with ethyl acetate, to give, after recrystallization from ethyl acetate, 260 mg (yield 59%) of the title compound as crystals, melting at 160°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[C:34](=[O:40])[CH2:33][CH2:32][CH2:31]2.C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]5[C:35](=[CH:36][C:37]=4[O:38][CH3:39])[C:34](=[O:40])[CH2:33][CH2:32][CH2:31]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1OCCCCl)CCCC2=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1OCCCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2=O
Yield: 117.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.78 g, 3.6 mmol), K2CO3 (0.60 g, 4.1 mmol), KI (100 mg), 6-(3-chloropropoxy)-7-methoxy-1-tetralone (0.87 g, 3.2 mmol), and acetonitrile (50 ml) was stirred at reflux under nitrogen for 17 hours. The cooled reaction was poured into 100 ml of water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgSO4 and concentrated to yield 1.7 g of a brown oil. The oil was purified by preparative HPLC (Waters Associates Prep LC/system 500) to afford 1.0 g of a light brown solid. This was combined with an additional sample (2.3 g total) and recrystallization from ethanol yielded 1.7 g. A subsequent recrystallization from ethanol gave 1.25 g (36%) of 6-[3-[4-(6-fluoro-1,2-benzisoxanol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetralone as a beige powder, m.p.=129°-131° C.