Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[Br:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:20])[CH:11]=1.C(NC(C)C)(C)C.C([Li])CCC.[NH4+].[Cl-]>O1CCCC1.CCCCCC.C(O)(=O)C>[Br:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH2:20][C:1]([O:5][CH2:6][CH3:7])=[O:8])[CH:11]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1cc(C(=O)O)c(C)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)Cc1cc(Br)c(C)cc1C(=O)O
Temperature: -78 °C

Procedure:
A solution of 1.7 ml (14 mmol) of diethyl carbonate and 2.3 g (10 mmol) of 4-bromo-2,5-dimethylbenzoic acid in 15 ml tetrahydrofuran is added dropwise, over 2.5 hours, to a solution cooled to −78° C., prepared from 4.2 ml (30 mmol) of diisopropylamine and 19 ml of a 1.6 molar n-butyl lithium solution in hexane, in 35 ml tetrahydrofuran. Then it is heated to 0° C., poured into 200 ml of 3% NH4Cl solution, adjusted to pH 6 with acetic acid and extracted with ethyl acetate. The ethyl acetate phase is washed with 14% NaCl solution and dried with Na2SO4. The solvent is distilled off and the residue remaining is triturated several times in a little diisopropylether/petroleum ether and then dried.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.CO[C:19]1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=C[CH:24]=1>C1COCC1>[Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH:12]([CH2:19][CH3:24])[CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCC(C)NC(=O)Nc1cc(C(N)=S)c(Br)cn1

Procedure:
The title compound was synthesized by a method analogous to the synthesis of Intermediate 42 starting with Intermediate 50 and Lawessons reagent in THF. MS (ESP): 332 (M+1) for C11H15BrN4OS
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:2]2[C:7]([NH2:8])=[CH:6][C:5]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][N:3]=2)[CH:20]=[N:21][CH:22]=1
Reactant: Nc1cc(N2CCOCC2)cnc1Cl
Reactant: COc1cncc(B(O)O)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cncc(-c2ncc(N3CCOCC3)cc2N)c1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
2-Chloro-5-morpholinopyridin-3-amine (0.26 g, 1.2 mmol), 5-methoxypyridin-3-ylboronic acid (0.24 g, 1.6 mmol), tricyclohexylphosphine (42.7 mg, 0.15 mmol), and tris(dibenzylideneacetone)dipalladium (0) (68.4 mg, 0.075 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (5.0 mL) and aq. 1.3M potassium phosphate tribasic (2.3 mL, 3 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-100% EtOAc in hexanes) to afford a brown solid as 5′-methoxy-5-morpholino-2,3′-bipyridin-3-amine. Mass Spectrum (pos.) m/e: 287.2 (M+1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br-].[C:12]([CH:15](C)[CH2:16][CH2:17][CH2:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:14])=[O:13]>C1COCC1>[C:2]1(/[CH:1]=[CH:19]\[CH2:18][CH2:17][CH2:16][CH2:15][C:12]([OH:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCCC/C=C\c1ccccc1
Reaction time: 8 h

Procedure:
Benzaldehyde (6.63 g, 0.062 mol, 6.35 ml) in dry THF (20 ml) was added dropwise to a stirred suspension of NaH (60% dispersion, 5.51 g, 0.138 mol) and (5-carboxyhexyl)-triphenylphosphonium bromide (30 g, 0.066 mol) in dry THF (260 ml). After stirring overnight, the solvent was evaporated to dryness, and the residue taken up into water (300 ml). The solution was made alkaline (pH 12-14) with NaOH solution (4 M) and extracted with EtOAc. The basic solution was then acidified (conc. HCl), extracted with Et2O, and the combined extracts washed with brine and dried with MgSO4. Removal of the solvent afforded 16.5 g of crude product which was purified by chromatography (silica, 1:5 EtOAc/petroleum ether, increasing to 1:1 EtOAc/petroleum ether toward completion) to give 10.81 g (85%) of E-/Z-7-phenylhept-6-ene-oic acid (˜1:1 mixture) as a pale yellow oil. Hydrogenation of the unsaturated acid (10% Pd—C, EtOAc) afforded the saturated compound (51): 1H NMR (CDCl3) δ 11.57 (br s, 1H), 7.20 (m, 5H), 2.58 (t, J=7.7 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 1.61 (m, 4H), 1.33 (m, 4H). 13C NMR (CDCl3), δ 180.8, 142.7, 128.5, 128.4, 125.7, 36.0, 34.2, 31.4, 29.0, 24.7.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(=[O:4])=[O:3].C(Cl)(C(Cl)=O)=O.[CH3:22][NH:23][CH3:24].C1COCC1>C(Cl)Cl.CN(C=O)C>[CH3:22][N:23]([CH3:24])[C:10]([C:9]1[CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=1[O:14][CH3:15])=[O:11]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)N(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-(chlorosulfonyl)-2-methoxybenzoic acid (1.243 g, 4.96 mmol) in dry DCM (20 ml) cooled to 0° C., (COCl)2 (1.302 ml, 14.88 mmol) was added drop-wise followed by few drops of dry DMF and the reaction was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure, treated with dry toluene (30 ml×2) and evaporated to dryness. The residue was suspended in dry toluene (20 ml) and the resulting suspension was cooled to 0° C.; a solution of dimethylamine 2.0 M in THF (4.96 ml, 9.92 mmol) was added drop-wise and the reaction was stirred at RT overnight. The mixture was diluted with DCM and washed with brine; the organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel (EtOAc/petroleum ether=60/40) to give 3-(dimethylcarbamoyl)-4-methoxybenzene-1-sulfonyl chloride (Int. 9) (400 mg, 1.440 mmol, MS/ESI+278.0 [MH]+).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5]CBr.[Mg].Cl[SiH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>C1COCC1>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][Si@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1
Reactant: FCCCCCBr
Reactant: Fc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: FCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
3.4 g (20 mmol) of fluoropentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.5 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-3,4-difluorobiphenyl to obtain 4'-(trans-4-(4-fluorobutyl)-4-silacyclohexyl)-3,4-difluorobiphenyl. The silacyclohexane rings of this product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 6.3 g of the trans isomers (yield 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:16])([CH3:15])[C:10](OCC)=[O:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:16])([CH3:15])[CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)(C)c1cccc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C(C)(C)CO)c1
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
To a solution of ethyl 2-(3-methoxyphenyl)-2-methyl-propanoate (Intermediate 38, 2 g, 9.0 mmol) in THF (20 mL) at 0° C., lithium aluminium hydride 2M in THF (9.0 ml, 18.0 mmol) was added and the resulting mixture was stirred for 20 minutes at the same temperature. The reaction was quenched with water (10 ml) (slow dropwise addition), and extracted with EtOAc (15 ml). The organic layer was washed with an aqueous 1N solution of HCl (10 ml), dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.439 g) that was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:23])[CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=3)[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2ccc(I)cc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3ccc(I)cc3)CC2)C1
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a solution of 4-hydroxy-4-(4-iodophenyl)cyclohexanone (624 mg, 2 mmol) in CH2Cl2 (10 mL) was added N-((3R)-pyrrolidin-3-ylcarbamoylmethyl)-3-trifluoromethylbenzamide (730 mg, 2 mmol) and then NaBH(OAc)3 (666 mg, 3 mmol). After stirred for 1 h, the reaction was quenched with 10% NaHCO3, and extracted with EtOAc. The organic extracts were combined, washed with saline solution, dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 1% NH4OH in ethyl acetate/methanol (100/0 to 10/90) to yield the major isomer (544 mg, 44.2%) and the minor isomer (446 mg, 36.3% yield). For the major isomer, LCMS: 615.2 (M+H+, 100%); 1H NMR: (CDCl3) δ 8.09, (s, 1H); 7.98, (d, 1H); 7.77, (d, 1H); 7.67, (d, 2H); 7.57, (t, 1H); 7.28, (d, 2H); 7.22, (t, 1H, NH); 6.44, (d, 1H, NH); 4.49, (m, 1H); 4.12, (m, 2H); 2.87, (m, 1H); 2.64, (m, 2H); 2.38, (m, 1H); 2.25, (m, 4H); 1.93, (m, 2H); 1.54-1.70, (m, 6H).
Reaction SMILES: [Cl:1]C1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][CH:15]=1.CO.Cl>ClCCl.C(OCC)C>[ClH:1].[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N+:20]([O-:6])=[CH:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2ccncc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2cc[n+]([O-])cc2c1
Reaction time: 3 h

Procedure:
At room temperature 58 g of m-chloroperoxybenzoic acid (purity 75%) were added in portions to a stirred solution of 7-methoxy-isoquinoline (35.9 g) in 500 mL of dichloromethane. Stirring was continued for 3 hours and subsequently methanol (400 mL) was added. The bulk was reduced to 300 mL and 325 mL of a saturated solution of hydrogen chloride in diethyl ether were added. Dilution with 600 mL of diethyl ether afforded precipitation of yellow crystals, which were separated by filtration, washed with chilled diethyl ether and dried in vacuo. Yield: 41.3 g (87%); m.p. 185-187° C.; (+)-FAB-MS: 176 (MH+-HCl).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[N:10][C:6]=2[CH:5]=[C:4]([O:17][C:23]2[CH:24]=[C:19]([Cl:18])[N:20]=[CH:21][N:22]=2)[CH:3]=1
Reactant: Oc1cc(Cl)c2[nH]c(C3CCOCC3)nc2c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Oc2cc(Cl)c3[nH]c(C4CCOCC4)nc3c2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.10 g (0.40 mmol) 7-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-ol and 60 mg (0.40 mmol) 4,6-dichloropyrimidine were placed in 2.0 mL DMF. 61 mg (0.40 mmol) potassium carbonate were added and the mixture was stirred overnight at RT. The reaction mixture was filtered and purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][C:11]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[O:13]2)[O:10][N:9]=1.O1CCOCC1.S(=O)(=O)(O)O>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]([OH:21])=[O:13])[O:10][N:9]=1
Reactant: Cc1ccccc1C1=NOC2(C1)OC(=O)c1ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cc(-c2ccccc2C(=O)O)on1
Yield: 92 %

Procedure:
A mixture of 0.26 g. of 3'-(2-methylphenyl)-spiro[isobenzofuran-1(3H),5'(4'H)-isoxazol]-3-one, 4ml. of water, 4 ml. of dioxane and 0.10 ml. of concentrated sulfuric acid was stirred at reflux for one hour, allowed to cool and diluted with 15 ml. of water. The resultant oil was stirred several minutes to give 0.24 g. of white solid; m.p. 162°-163.5° C. in 92% yield.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[N:24]1([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C.CN1CCCC1=O.O1CCCC1.O.O.[OH-].[Li+]>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[N:23][C:2]([N:27]5[CH2:28][CH2:29][N:24]([CH2:30][C:31]([OH:33])=[O:32])[CH2:25][CH2:26]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(=O)O)CC3)cc1OCC2
Temperature: 25 °C

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 (80.0 mg, 0.242 mmol), ethyl 2-(piperazin-1-yl)acetate (0.275 g, 1.60 mmol) and Triethylamine (0.400 mL, 2.87 mmol) in N-Methylpyrrolidinone (4.36 mL, 45.2 mmol) was heated at 150° C. for 2 days. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water, brine. The organic layer was dried Na2SO4, concentrated. To a solution of crude ethyl ester intermediate in Tetrahydrofuran (3.00 mL, 37.0 mmol) and Water (3.00 mL, 166 mmol) was added Lithium hydroxide hydrate (0.0406 g, 0.967 mmol). The reaction was stirred at r.t. The reaction was quenched with water then wash EtOAc. The aqueous layer was concentrated to give 2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid which was carried to next reaction. MS: (ESI+)=439.2
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:39][CH:40]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]3[C:2]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[N:39][CH:40]=4)=[N:3][CH:4]=[CH:5][CH:6]=3)[N:9]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
4-(2-Fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.150 g, 0.337 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (0.0841 g, 0.402 mmol) were dissolved in THF (3 mL). The mixture was cooled to 0° C. and LiHMDS (Acros) (1.4 mL, 1.4 mmol) was added slowly. The dark red mixture was stirred at 0° C. for 1 h. The reaction mixture was partitioned between saturated aqueous ammonium chloride (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (25 g, eluent: EtOAc in hexanes 0%-50%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.145 g, 68% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.83 (s, 1H); 8.76-8.87 (m, 1H); 8.39-8.48 (m, 1H); 8.25-8.34 (m, 1H); 7.91-8.03 (m, 1H); 7.76-7.87 (m, 1H); 7.10-7.24 (m, 5H); 6.86 (t, J=7.09 Hz, 4H); 6.70-6.81 (m, 1H); 4.83 (br. s., 4H); 3.80 (d, J=5.70 Hz, 6H); 2.58 (s, 3H); 1.53 (s, 9H). m/z (ESI, +ve ion) 635.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](O)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.C1C=CC2N(O)N=[N:27]C=2C=1.CCN=C=NCCCN(C)C.Cl.N.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:27])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1
Reactant: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxylic acid (36 mg, 0.1 mmol) in DCM (5 mL) was added HOBt (16 mg, 0.12 mmol), and EDC.HCl (23 mg, 0.12 mmol) and 2 M NH3 in methanol (0.2 mL, 0.4 mmol). The mixture was kept overnight at RT. The mixture was concentrated, and EtOAc and aq. NaHCO3 were added. The aqueous layer was extracted with ethyl acetate once. The combined organic layers were dried (MgSO4) and concentrated to give 36 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cn1nnn(-c2c(Cl)ccc(C(=O)O)c2Cl)c1=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1nnn(-c2c(Cl)ccc(C(=O)Cl)c2Cl)c1=O
Yield: 100.3 %

Procedure:
2,4-Dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoic acid (3.42 g) and thionylchloride (4.22 g) were added to 1,2-dichloroethane (50 ml). The mixture, after adding several drops of N,N-dimethylformamide, was refluxed upon heating for 4 hours. After cooling, the solvent was distilled off to obtain crude 2,4-dichloro-3-(4,5-dihydro4-methyl-5-oxo-1H-tetrazol-1-yl)benzoyl chloride (3.65 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH:15]([CH3:20])[C:16](OC)=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH2:25]([NH2:29])[CH2:26][CH2:27][CH3:28].Cl>C1C=CC=CC=1>[CH2:25]([NH:29][C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:8][N:7]=2)=[CH:22][CH:21]=1)[CH3:20])[CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCCCN
Agent: Cl
Solvent: c1ccccc1
Product: CCCCNC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
A mixture containing 17.1 g (0.05 mol) of methyl 2-[4-(5-trifluoromethyl-2-pyridyloxy)-phenoxy]-propionate and 7.3 g (0.1 mol) of n-butylamine is heated at 80°-85° C. for 6 hours while stirring, then cooled and diluted with 50 ml of benzene. The benzene solution is shaken with 5% aqueous hydrochloric acid solution and then washed with water to acid-free. After separation the organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The crude product can be recrystallized from a mixture of benzene with petroleum ether (b.p. 70° C.) The compounds Nos. 1, 6, 7 and 8 are similarly prepared from the corresponding starting materials.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=[O:6])[CH2:3][CH2:2]1.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Mg]Br.[NH4+].[Cl-].O>C1COCC1>[CH:1]1([CH2:4][CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[OH:6])[CH2:3][CH2:2]1
Reactant: O=CCC1CC1
Reactant: Br[Mg]c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: OC(CC1CC1)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyclopropylacetaldehyde (1.00 g, 11.89 mmol, purchased from Beta Pharma, Inc., Branford, Conn.) in THF (15 mL) at 0° C. under N2 was added 2-pyridylmagnesium bromide (47.6 mL×0.25 M, purchased from Rieke Metals, Inc., Lincoln, Nebr.) dropwise over 15 min. The mixture was stirred at 0° C. after 30 min, allowed to warm to rt and stirred at rt for 3.5 hr. To the reaction mixture was added saturated aqueous NH4Cl solution (5 mL) followed by water (15 mL). The mixture was extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4. After removal of organic solvents, purification of the residue by flash chromatography on silica gel with 40-70% EtOAc/hexanes the title compound was obtained as a white solid. Mass Spectrum (ESI) m/z=164.1 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:19](=O)[CH2:18][O:17][CH:16]([CH2:21][N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]2=3)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:21][N:22]2[C:23]3[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=3[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=3)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COC(CN2c3ccccc3CCc3ccccc32)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCOC(CN3c4ccccc4CCc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (0.03 g) in tetrahydrofuran (5 ml) was added a solution of 5-(4-benzyl-5-oxo-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz-[b,f]azepine (0.5 g) in tetrahydrofuran (15 ml) under ice cooling, and the resulting mixture was stirred at room temperature for 1 hour and refluxed for 10 hours with stirring. The reaction mixture was cooled, admixed with water (2 ml) and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-benzyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 139°-140° C (oxalate).