Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19][CH2:20][CH3:21])=[CH2:18])CCC>O1CCOCC1.CCOC(C)=O.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>[CH2:20]([O:19][C:17]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[CH2:18])[CH3:21]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C(OCC)c1ccc(C(=O)OC)nc1
Yield: 84.9 %

Procedure:
To a solution of methyl 5-bromopyridine-2-carboxylate (25 g, 116 mmol) in dioxane (30 mL) was added Pd(PPh3)4 (6.7 g, 5.8 mmol) and tributyl(1-ethoxyvinyl)tin (46 g, 127.0 mmol). The resulting solution was heated to reflux under N2 for 12 h. Upon completion of the reaction as judged by LC/MS analysis, the reaction was diluted with EtOAc, washed with KF solution (10% aqueous), filtered through Celite, dried over MgSO4, filtered, concentrated and purified on silica gel to afford the title compound (20.4 g). LC/MS: m/e 208.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)C.[Cl:7][C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C>O>[Cl:7][C:8]1[N:13]=[C:12]([N:2]([CH3:3])[CH3:1])[CH:11]=[CH:10][N:9]=1
Reactant: CNC
Reactant: Clc1ccnc(Cl)n1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a 20% dimethylamine-ethanol solution (15.4 g) of 2,4-dichloropyrimidine (3.0 g) was added triethylamine (3 ml) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:1) to give the title compound (1.90 g) as white crystals, m.p.=77-79° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[C:15]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:14][CH:13]=[N:12]2)=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.C(OC(=O)C)(=O)C.[N+:28]([O-])([OH:30])=[O:29]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:11]2[C:15]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[C:14]([N+:28]([O-:30])=[O:29])[CH:13]=[N:12]2)=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)Nc1ccnn1-c1nn2c(c1Cl)CCCC2
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1nn2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
8.72 g (29.7 mmol) N-[1-(3-Chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-5-pyrazolyl]propionamide was suspended in 33 ml acetic acid. Under ice cooling, at 0°-5° C., 3.31 g (32.5 mmol) acetic anhydride was added. 1.93 g (31 mmol) Fuming nitric acid was added dropwise. After stirring for 6 hours at room temperature, the mixture was concentrated. The residue was taken up in dichloromethane, neutralised with aqueous sodium hydrogen carbonate and washed with aqueous sodium chloride. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:20]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH3:20])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(NC(=O)OC(C)(C)C)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Br)cn(C)c1=O
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)carbamate (150.0 mg, impure) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mol, 60% in oil) in portions at 0° C. It was stirred for 30 min. Then CH3I (231.0 mg, 1.5 mmol) was added dropwise at 0° C. The reaction mixture was stirred for 2 h at 30° C. The reaction was quenched with saturated aqueous NH4Cl (15 mL), extracted with EA (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the title compound (120.0 mg, crude) as a green solid, which was used directly in the next step without purification.
Reaction SMILES: [BrH:1].[NH2:2][CH:3]1[C:15](=[O:16])[N:5]2[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH3:11])[CH2:8][S:9](=[O:10])[C@H:4]12.[CH3:17][C:18]([CH3:20])=O>C(O)(=O)C>[Br-:1].[C:12]([C:6]1[N:5]2[C:15](=[O:16])[CH:3]([NH+:2]=[C:18]([CH3:20])[CH3:17])[C@H:4]2[S:9](=[O:10])[CH2:8][C:7]=1[CH3:11])([OH:14])=[O:13]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2S(=O)C1
Reactant: CC(C)=O
Reactant: Br
Solvent: CC(=O)O
Product: CC(C)=[NH+]C1C(=O)N2C(C(=O)O)=C(C)CS(=O)[C@H]12
Product: [Br-]
Yield: 79 %

Procedure:
With stirring 0.4 ml of a hydrogen bromide solution (33%) in acetic acid was added to 1 g (2.1 mmoles) of 7-amino-3-methyl-1-oxo-3-cephem-4-carboxylic acid at 0° C. After adding gradually 5 ml of acetone a crystalline precipitate was obtained, which was filtered off, washed with acetone and dried giving 0.60 g (79%) of the title product.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=4)[C:39](O)=[O:40])[O:33][C:34]=3[CH3:35])=[C:26](OC)[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl.C([N:52]=C=NCCCN(C)C)C.CN(C)[CH:63]=[O:64]>O>[C:39]([C:38]1[CH:37]=[C:36]([C:32]2[O:33][C:34]([CH3:35])=[C:30]([CH2:29][O:28][C:27]3[CH:45]=[CH:46][C:24]([CH2:23][O:22][C:12]4[C:11](/[CH:10]=[CH:9]/[P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[CH:15][N:14]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:13]=4)=[CH:25][C:26]=3[O:64][CH3:63])[N:31]=2)[CH:44]=[CH:43][CH:42]=1)(=[O:40])[NH2:52]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)O)c3)oc2C)c(OC)c1)OCC
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(N)=O)c3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
A mixture of 3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid (1.09 g), 1-hydroxybenzotriazole ammonia complex (0.37 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-(3-{[4-({2-[3-(carbamoyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenylphosphonate as colorless crystals (0.82 g, yield 76%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][CH2:14][NH2:15].[CH3:16][O:17][C:18]([C:20]1[N:21]=[C:22]([Cl:29])[N:23]([CH3:28])[C:24]=1[C:25](O)=[O:26])=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[N:21]=[C:22]([Cl:29])[N:23]([CH3:28])[C:24]=1[C:25](=[O:26])[NH:15][CH2:14][CH2:13][C:5]1[N:4]([CH3:3])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)=[O:19]
Reactant: Cn1c(CCN)nc2ccccc21
Reactant: COC(=O)c1nc(Cl)n(C)c1C(=O)O
Agent: Cl
Product: COC(=O)c1nc(Cl)n(C)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine dihydrochloride (125 mg, 504 μmol) and 2-chloro-1-methyl-1H-imidazole-4,5-dicarboxylic acid 4-methyl ester (172 mg, 787 μmol) according to the method described in example 8, step 3 as purple solid (77 mg, 205 μmol, 40.7%). MS: M=376.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@@H:45]([C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[Cl:53][C:50]1[CH:49]=[CH:48][C:47]([C@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]2[C@@H:25]2[C@@:20]([CH3:54])([CH2:21][CH2:22]3)[C@@:19]3([CH3:55])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH3:46])=[CH:52][CH:51]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccc(Cl)cc2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((R)-1-(4-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (2.5 g, 3.05 mmol) in Dichloromethane (20 mL) was added TFA (13 mL, 3.05 mmol). The reaction mixture was stirred at r.t. for 2 hs and evaporated in vacuo to afford crude product, which was diluted with DCM, washed with water, saturated NaHCO3 twice, water, 2 M HCl, water, and the organic layer was concentrated, diluted with MeOH/H2O (1:5, 36 mL) and freeze-dried under high vacuo to give the product 4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((R)-1-(4-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (1.7 g, 2.217 mmol, 72.6%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) d=12.34-12.04 (m, 1H), 8.43 (d, J=7.8 Hz, 1H), 7.53-7.18 (m, 4H), 6.63 (d, J=15.8 Hz, 1H), 5.92 (d, J=15.8 Hz, 1H), 4.94 (quin, J=7.0 Hz, 1H), 4.39 (dd, J=4.6, 10.9 Hz, 1H), 3.18 (dt, J=6.7, 13.7 Hz, 1H), 2.70 (dd, J=4.3, 10.5 Hz, 2H), 2.58-2.52 (m, 1H), 2.34-1.99 (m, 3H), 1.99-0.56 (m, 48H); LC/MS: m/z calculated 761.4. Found 762.3 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.S(Cl)([Cl:17])=O.CN(C=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[CH:6]=[CH:5]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc2cc(Br)ccc2c1
Temperature: 60 °C

Procedure:
A suspension of 6-bromo-2-naphthoic acid (100 g), thionyl chloride (37.7 mL) and DMF (0.5 mL) in THF (1000 mL) was stirred with heating at 60° C. for 90 min. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The obtained solid was dissolved in toluene and the solvent was evaporated to give a pale-yellow powder of 6-bromo-2-naphthoyl chloride.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[P:27](OCl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[C:1]([CH:3]([P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Reactant: CCOP(=O)(OCl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C#N)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
In a 100 ml 3 necked round bottom flask, intermediate tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate (7 g) was taken in dry THF (125 ml) under nitrogen. lithium bis trimethylsilyl amide (10.8 g) was added dropwise at −78° C. and stirred for 1 hr, then diethyl chloro phosphate (5.84 g) in 5 ml dry THF was added drop wise to the above reaction mixture. Reaction mixture was stirred at −78° C. for 1 hour. TLC was checked no starting material and the reaction mixture was quenched with saturated ammonium chloride (250 ml) and ethyl acetate was added. The organic layer was washed with brine, dried and concentrated. The crude product was purified by column chromatography using 230-400 silica gel 2.5% methanol\chloroform as eluent to give compound tert-butyl 4-(cyano(diethoxyphosphoryl)methyl)piperazine-1-carboxylate as yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35](O)[CH2:36][CH2:37][CH2:38][CH2:39]C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:18][CH:17]=1
Reactant: CCCCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCOC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 96.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-hexanol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (69 mg, yield 82%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[H-].[Na+].Br[CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[O:22])[CH2:15][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2)[CH3:21]
Reactant: CCOC(=O)C(=O)CBr
Reactant: c1ccc2c(c1)CCCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CN1CCCCc2ccccc21

Procedure:
Add 2,3,4,5-tetrahydro-1H-benzo[b]azepine in small portions to a 0° C. suspension of 60% sodium hydride (3.0 g, 0.12 mol) in 300 mL of dimethylformamide. Upon complete addition of the amine, remove the ice bath and stir the reaction at 20-24° C. for 40 minutes. Add ethyl bromopyruvate (22.6 mL, 0.16 mol) and stir the resulting mixture at 20-24° C. for 6 hours. Add an additional 5 mL of ethyl bromopyruvate and stir the mixture for 1 hour. Quench by adding 50 mL of water then dilute with 1.5 L of dichloromethane. Separate the layers, wash the organic layer sequentially with water (2×500 mL) and saturated aqueous sodium chloride (500 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure at 60° C. Dissolve the residue in ethyl acetate (500 mL), wash sequentially with water (3×100 mL) and saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5-10% EtOAc/hexanes to provide the desired compound as an off white solid (7.0 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=[C:14]3N=N2)=[N:6][CH:7]=1.[OH2:28].[OH-].[NH4+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:15]2[C:14]([OH:28])=[CH:19][C:18]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][N:16]=2)=[N:6][CH:7]=1
Reactant: O
Reactant: Cc1cc(Br)cnc1CCCn1nnc2cc(Cc3cccnc3)cnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1O

Procedure:
3-[3-(5-Bromo-3-methylpyrid-2-yl)propyl]-6-(3-pyridylmethyl)-3H-1,2,3-triazolo[5,4-b]pyridine (2.68 g) was added in portions over 15 minutes to hot (190°-200° C.) stirred polyphosphoric acid (10.45 g). The stirred reaction was heated at 190°-200° C. for a further 45 minutes, water (20 ml) was added to the hot reaction mixture, the solution was neutralised with concentrated ammonium hydroxide and allowed to cool. The pH was then raised to 10, chloroform extraction of the aqueous mixture gave a brown solid. This solid was recrystallised from ethanol/ether giving buff crystals (1.64 g). These were chromatographed on silica in methanol/chloroform 1:9, the product was then recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (1.4 g) (off-white crystals), m.p. 141°-143° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1

Procedure:
7-Acetoxyisoflavone was prepared from 7-hydroxyisoflavone (2.6 g, 10.9 mmol), acetic anhydride (16 ml) and pyridine (3.0 ml) as described for 4′,7-diacetoxydaidzein. Yield: (2.5 g, 82%) m.p. 133° C. 1H NMR (CDCl3): δ 2.36 (s, 3H, OCOCH3), 7.18 (dd, 1H, J 2.2 Hz 8.6 Hz, H6), 7.31 (d, 1H, J 2.2 Hz H8), 7.39-7.57 (m, 5H, ArH), 8.00 (s, 1H, H2), 8.33 (d, 1H, J 8.6 Hz, H5). Mass spectrum: m/z 280 (M, 28%); 237-(98); 238 (57).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1N1C=NC(C(F)(F)F)=N1)=[O:11].CC1C=CC([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:38]1[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=1)=[O:11]
Reactant: Cc1ccc(-c2ccnc(C)c2)c(C(=O)O)c1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccnc(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(2-methylpyridin-4-yl)benzoic acid. ESI-MS (m/z): 338 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[CH2:39]O.C(Cl)Cl>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:39][C:38]2[CH:37]=[C:36]([Cl:35])[CH:43]=[C:42]([Cl:44])[CH:41]=2)[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)c1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of 5.11 g (19.1 mmole) of N-benzyl-3-(S)-phenylmorpholine-2-one (from Example 14) in 100 mL of dry THF was cooled to -75° C. under nitrogen and was treated dropwise with 20.5 mL (20.5 mmole) of a 1M solution of lithium tri(sec-butyl)borohydride (L-Selectride®) in THF. After stirring the solution at -75° C. for 30 min, a solution of 3,5-dichlorobenzyl alcohol, trifluoromethanesulfonate ester in toluene (from Example 44, Step A) was added by cannula so that the on 67 g of silica eluting with 1.5 L of 100:1 methylene chloride: methanol, and the rich cuts were purified by flash chormatography on 32 g of silica eluting with 50:50 hexanes: ethyl acetate and then 50:50:5 hexanes:ethyl acetate:methanol to give 0.051 g (20%) of an oil, which by 1H NMR was pure cis morpholine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:17][C:13](=[O:16])/[CH:14]=[CH:15]/[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:6]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(O)c1cc(Br)cnc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c(C(C)(C)O)c1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-(2-Amino-5-bromo-pyridin-3-yl)-propan-2-ol (200 mg, 0.86 mmol), tert-butyl acrylate (628 μL, 4.3 mmol) and (i-Pr)2EtN (452 μL, 2.6 mmol) in DMF (10 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (19.4 mg, 0.09 mmol) and P(o-tol)3 (51.7 mg, 0.18 mmol) then heated to 110° C. for 20 h. The hot mixture was filtered through a pad of celite. The filtrate was diluted with H2O (100 mL) then extracted with ethyl acetate (2×100 mL). The combined organic fractions were dried over MgSO4, and subjected to flash chromatography on silica gel using 50% ethyl acetate:hexanes. The appropriate fractions were collected and concentrated to yield a yellow crystalline solid. Yield: 153 mg (64%); 1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.1 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.45 (d, J=15.8 Hz, 1H), 6.69 (s, 2H), 6.32 (d, J=15.8 Hz, 1H), 5.53 (s, 1H), 1.52 (s, 6H), 1.48 (s, 9H); ESI MS m/z 279 [C15H22N2O3+H]+