Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:9]3[O:10][C:11]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=4[CH:8]3[C:6]=2[CH:7]=1.C1C(=O)N([Br:26])C(=O)C1.[Al]>CN(C=O)C>[Br:26][C:4]1[C:5]2[O:18][CH:9]3[CH:8]([C:6]=2[CH:7]=[C:2]([CH3:1])[CH:3]=1)[C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[O:10]3
Reactant: Cc1ccc2c(c1)OC1Oc3ccc(C)cc3C21
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)OC1Oc3c(Br)cc(C)cc3C21
Reaction time: 72 h

Procedure:
The backbone 2,8-dimethyl-5a,10b-dihydrobenzofuro-[2,3-b]benzofuran (1.5 g, 6.3 mmol) and NBS (2.016 g, 11.3 mmol) are dissolved in DMF (100 mL) and stirred at RT for 1 day (flask is covered with aluminium foil). The conversion is monitored by GC/MS. After three days, a mixture of the monobrominated product, the dibrominated product, and the unmodified backbone (monobromo/dibromo/backbone) is formed, in a 75/23/2 ratio, based on weight percents. The solvent is evaporated to dryness and the solid is washed with water and extracted with dichloromethane. The dichloromethane solution is then dried over MgSO4 and evaporated to dryness. The solid obtained is washed with ethanol to give a white solid (1.5 g, containing a mixture of monobromo/dibromo, 75/25). This product (“bromobackbone”) is used in step (b) without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[N:11][C:12](=O)[NH:13][N:14]=2)[CH:4]=1.C(Cl)(Cl)[Cl:19].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:19][C:12]1[N:13]=[N:14][C:9]([C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[CH:7][CH:6]=2)=[CH:10][N:11]=1
Reactant: O=c1ncc(-c2cccc(C(F)(F)F)c2)n[nH]1
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2cnc(Cl)nn2)c1

Procedure:
A 37.2 g. portion of 6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazin-3(2H)-one in 250 ml. of chloroform is refluxed overnight and then cooled. A 250 ml. portion of phosphorus oxychloride and 1.7 g. of N,N-dimethylformamide are added and the mixture is refluxed for 4.5 hours and then concentrated to a brown oil. This oil is dissolved in methylene chloride and poured into ice-water. The mixture is filtered through silica gel giving crystals which are recrystallized from hexane, giving 3-chloro-6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine as reddish plates.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](OCC)=[O:7])[N:3]2[CH:11]=[N:12][CH:13]=[C:2]12.[BH4-].[Na+].CC(C)=O>CO>[OH:7][CH2:6][C:4]1[N:3]2[CH:11]=[N:12][CH:13]=[C:2]2[S:1][CH:5]=1
Reactant: CCOC(=O)c1csc2cncn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: OCc1csc2cncn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.80 g of the ethyl imidazo[5,1-b]-thiazole-3-carboxylate prepared in Preparation 11 in 16 ml of methanol was added 400 mg of sodium borohydride, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added dropwise 3 ml of acetone. The mixture was stirred for 30 minutes, and then concentrated to dryness under reduced pressure. To the residue were added 20 ml of methylene chloride and 20 ml of a saturated saline solution, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (20 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.615 of the title compound as light brown crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(O)CCC.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCCCO
Solvent: CCCCO
Solvent: O
Product: OCCCNc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
2,4-Dichloropyrimidine (4.5 g, 0.03 m) in an n-butanol (50 ml)-water (50 ml) mixture is reacted with 3-amino-1-propanol (4.5 g, 0.06 m) following the procedure of Example 1. After stirring at room temperature for 24 hours, water (200 ml) is added, the mixture is extracted with methylene chloride (3×200 ml), the combined organic extracts are washed well with water, dried, and concentrated. Recrystallization of the solid residue from methylene chloride/hexane yields 2.8 g of 2-chloro-4-(3-hydroxypropylamino)pyrimidine, m.p. 113°-114° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:30]=[C:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[C:42]([CH:43]=O)=[CH:41][CH:40]=[CH:39][N:38]=1>O1CCCC1.CO>[CH3:2][O:3][CH:4]=[CH:43][C:42]1[C:37]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C:31]2=[O:30])=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccnc1N1CCCCC1=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COC=Cc1cccnc1N1CCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
Methoxymethyl-triphenylphosphonium chloride (3.59 g, 10.48 mmol, 1.3 eq) is dissolved in dry tetrahydrofuran (150 ml) under nitrogen. This solution is cooled at 0° C. and potassium tert-butoxide (1.085 g, 9.67 mmol, 1.2 eq) is added. The reaction mixture is stirred at 0° C. for 30 min. A solution of crude 2-(2-oxopiperidin-1-yl)pyridine-3-carbaldehyde a4-1 (4.2 g, 8.06 mmol, 1 eq) in dry THF (50 ml) is added, then the reaction mixture is warmed up to room temperature and stirred for 1 hour. The solvent is removed under reduced pressure, the residue is taken with ethyl acetate, stirred, filtered and the solid cake washed with ethyl acetate (2 times). The filtrate is evaporated under reduced pressure. The residue is purified by chromatography over silicagel (gradient: CH2Cl2/MeOH/NH4OH 100/0/0 to 97/3/0.3). The product obtained is redissolved in methanol, catched over an acidic column, washed with methanol and then released with ammonia 1M in methanol. The solvent is evaporated under reduced pressure to afford 540 mg of 1-[3-(2-methoxyethenyl)pyridin-2-yl]piperidin-2-one a4-2.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:12]([CH3:11])[CH2:13][CH2:14][OH:15])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: CNCCO
Solvent: C1CCOC1
Product: COc1nc(N(C)CCO)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (5 g, 22.4 mmol) and 2-(methylamino)ethanol (2.19 g, 29.1 mmol) in THF (40 mL) was stirred for 18 h at rt and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 3:2) to afford 5.38 g of the title compound. tR: 0.84 min (LC-MS 2); ESI-MS: 262.1/264.1 [M+H]+ (LC-MS 2); Rf: 0.15 (hexane/EtOAc 3:2).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:33]=[C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31](=[O:32])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(4-ethylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 12, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=[N:32][O:33][CH3:34])[C:7]([NH:9][CH:10]2[C:30](=[O:31])[N:12]3[C:13]([C:17]([O:19]CC4C=CC([N+]([O-])=O)=CC=4)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]23)=[O:8])[N:3]=[N:2]1>CO.O1CCCC1.[C].[Pd]>[S:1]1[CH:5]=[C:4]([C:6](=[N:32][O:33][CH3:34])[C:7]([NH:9][CH:10]2[C:30](=[O:31])[N:12]3[C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH2:15][S:16][C@H:11]23)=[O:8])[N:3]=[N:2]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csnn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csnn1
Reaction time: 3.5 h
Yield: 24.8 %

Procedure:
10% Palladium carbon (0.85 g.) was added to a solution of p-nitrobenzyl 7-{2-(1,2,3-thiadiazol-4-yl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylate (syn isomer, 1.65 g.) in methanol (70 ml.) and tetrahydrofuran (90 ml.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 3.5 hours. After removing the catalyst from the reaction mixture by filtration, the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was adjusted to pH 7 to 8 with sodium bicarbonate, washed with ethyl acetate, adjusted to pH 1.5 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was pulverized with diethyl ether. The precipitates were collected by filtration and the dried to give yellow powder of 7-{2-(1,2,3-thiadiazol-4-yl)-2-methoxyiminoacetamido}-3-cephem- 4-carboxylic acid (syn isomer, 0.3 g.), m.p. 200° to 210° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8](Br)(Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].CC(C)=[O:24]>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8](=[O:24])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(Br)(Br)COc1ccc(Br)cc1-2
Reactant: CC(C)=O
Solvent: O
Product: COC(=O)c1nc2c(s1)C(=O)COc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
The mixture of 4,4,9-Tribromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (9.0 g, 18.07 mmol) in acetone (250 mL) and water (250 mL) was stirred at room temperature for 4 h. Then the mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated to afford the crude product which was triturated with EtOAc and hexane (EtOAc/hexane=1/5). After filtration, the solid was dried in vacuo to afford compound 9-Bromo-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (5.5 g, 86%) as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[O:5][CH2:6][CH2:7][N:8]=1)(C)=[CH2:2].[S:9](=[O:12])([OH:11])[O-:10].[Na+]>>[C:4]([NH:8][CH2:7][CH2:6][S:9]([OH:12])(=[O:11])=[O:10])(=[O:5])[CH:1]=[CH2:2]
Reactant: C=C(C)C1=NCCO1
Reactant: O=S([O-])O
Agent: [Na+]
Product: C=CC(=O)NCCS(=O)(=O)O

Procedure:
A process of claim 1 wherein a homopolymer of 2-isopropenyloxazoline is reacted with sodium bisulfite in order to provide a homopolymer of 2-acrylamido-ethane-1-sulfonic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]([F:20])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][CH:10]1[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1CCNCC1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 1-tert-butoxycarbonyl-3-fluoro-4-piperidinylacetate (653 mg, 2.26 mmol) in CH2Cl2 (10 mL) was added TFA (5 mL) at 0° C. After being stirred at room temperature for 4 hr, the reaction mixture was concentrated. The residue was taken up with sat. NaHCO3 solution and extracted with THF-EtOAc (1:1, v/v). The extracts were dried over MgSO4 and concentrated to afford ethyl 3-fluoro-4-piperidinylacetate (420 mg, 98%) as a yellow oil. 1H-NMR (CDCL3) δ 1.26 (t, J=7.4 Hz, 3H), 1.68–1.80 (m, 2H), 2.18 (m, 1H), 2.32 (dd, J=16.6, 6.8 Hz, 1H), 2.54 (dd, J=16.6, 7.5 Hz, 1H), 2.82 (m, 1H), 2.90, 3.00 (each d, J=14.4 Hz, total 1H), 3.31 (m, 1H), 3.51 (m, 1H), 4.15 (q, J=7.4 Hz, 2H), 4.82, 4.71 (each broad s, total 1H).
Reaction SMILES: [C:1]([C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[NH3:15].C[O-].[Na+]>CO>[NH:14]=[C:13]1[C:12]2[CH:11]=[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][C:3]=2[C:1](=[NH:15])[NH:2]1
Reactant: N#Cc1cc2ccccc2cc1C#N
Reactant: N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N=C1NC(=N)c2cc3ccccc3cc21

Procedure:
That is, α, α, α', α'-tetrabromo-o-xylene [the formula (V)] in an amount of 0.1 mol and fumaronitrile in an amount of 0.178 mol are reacted at 75° C. for 7 hours in the presence of 0.67 mol of sodium iodide in anhydrous N,N-dimethylformamide to yield 2,3-dicyanonaphthalene of the formula (VI). Subsequently, 57.3 mmol of the 2,3-dicyanonaphthalene is reacted with ammonia in the presence of sodium methoxide in methanol with heating for 3 hours to yield 1,3-diiminobenzo(f)isoindoline of the formula (VII). Further, 30.6 mmol of the 1,3-diiminobenzo(f)-isoindoline was reacted with 47.1 mmol of silicon tetrachloride in anhydrous tetralin and anhydrous tri-n-butylamine under reflux for about 3 hours to give dichlorosilicon naphthalocyanine [SiNcX2 (X=Cl)] which can be represented by the formula (II) except that the two OHs are replaced by two Cl's. Then, this compound is treated with concentrated sulfuric acid and then concentrated ammonia water to give dihydroxysilicon naphthalocyanine [SiNcX2 (X=OH)] of the formula (II).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[C:17]1(=[O:22])[O:21][CH2:20][CH2:19][CH2:18]1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[OH:22][CH2:17][CH2:18][CH2:19][C:20]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)=[O:21]
Reactant: Brc1ccc2ccccc2c1
Reactant: O=C1CCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCCO)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of 2-bromonaphthalene (10.77 g) in THF (150 ml) was added n-BuLi in hexane (1.65M, 36 ml) and the mixture was stirred at −78° C. for 30 minutes. To the solution was added γ-butyrolactone (25 ml) and the mixture was stirred at −78° C. for 1 minute. Aqueous solution of NH4Cl was added and the mixture was extracted with ethyl acetate. The extract was washed with aqueous NH4Cl solution, water and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane:ethyl acetate=3:1) followed by recrystallization from cyclohexane-ethyl acetate to give the titled compound (6.71 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:56])[C:35]([CH3:55])([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)C>C(O)C>[CH3:55][C:35]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:49][CH:50]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:39][CH:38]=1)[C:34]([OH:56])=[O:33]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3cccs3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 10 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl)-ethyl ester(0.132 mmol) (see Ex. 5, Part B) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 15, Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 95:5 CH2Cl2:MeOH to produce a white solid (10%). MS [EI+] 596 (M+H)+, [EI−] 594 (M−H)+
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:21]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH:2]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cn2cc(Cc3ccccc3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-((1H-indol-1-yl)methyl)benzoate 1 (0.250 g, 0.94 mmol) and benzaldehyde (96 μL, 0.94 mmol) in DCM (10 mL) at 0° C. was added SiEt3H (0.45 mL, 2.83 mmol) followed by trifluoroacetic acid (0.14 mL, 1.88 mmol). The reaction was stirred at 0° C. for 1 h. The reaction was then adjusted to pH 10 with 2 N NaOH and the organic products were extracted with DCM (3×15 mL). The combined organic fractions were washed with brine (15 mL), dried with Na2SO4, filtered and concentrated in vacuo. The title compound was isolated using automated column chromatography method 1 (0.262 g, 78%). 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.32-7.27 (m, 4H), 7.23-7.10 (m, 6H), 6.87 (s, 1H), 5.33 (s, 2H), 4.15 (s, 2H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.8, 143.0, 141.2, 136.8, 130.1, 129.5, 128.7, 128.4, 128.3, 126.6, 126.5, 126.0, 122.1, 119.5, 119.3, 115.4, 109.6, 52.2, 49.7, 31.6.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH2:6]([N:13]=[C:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+]>ClCCl>[CH2:3]([C:14]1([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:23][CH2:22][C:17]2([O:18][CH2:19][CH2:20][O:21]2)[CH2:16][CH2:15]1)[CH:2]=[CH2:1]
Reactant: c1ccc(CN=C2CCC3(CC2)OCCO3)cc1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCC1(NCc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 1 M solution of allylmagnesium bromide (127 ml, 127 mmol) was added dropwise to a solution of benzyl-(1,4-dioxaspiro[4.5]dec-8-ylidene)amine (15.6 g, 63.7 mmol) in dichloromethane (120 ml), and the reaction mixture was stirred for 72 h at room temperature. The mixture was then poured carefully onto saturated ammonium chloride solution (100 ml), while cooling with ice, and extraction with dichloromethane (3×40 ml) was carried out. The combined organic phases were dried with sodium sulfate and concentrated in vacuo, and the residue was purified by flash chromatography (400 g, 20×7.6 cm) with chloroform/methanol (10:0.2).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][C@@H:10]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][C@@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][CH:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@@H](C1)OCC(=O)N2Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2C(C1)OCCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-tert-butyl 1-benzyl-2-oxooctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate (126 g, 346 mmol) in anhydrous THF (2 L) was added borane methylsulfide complex (109 mL, 1.038 mol) drop wise at 0° C. The mixture was stirred at room temperature overnight. Methanol (300 mL) was added to the mixture at room temperature and heated to reflux for 1 h. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford tert-butyl 1-benzyloctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate as a mixture of trans diastereomers.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)=[CH:24][C:22]=3[CH:23]=2)=[O:16])=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:43][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)=[CH:24][C:22]=3[CH:23]=2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ccccn4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4cccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 59.9 %

Procedure:
To a solution of N-[4-(2-pyridylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (200 mg) in tetrahydrofuran (10 ml) was added 3-chloro-perbenzoic acid (70%, 0.18 g) at 0° C., and the mixture was stirred at room temperature for 17 hours. To the reaction mixture was added sodium thio-sulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated to give crystals, which were collected by filtration and was recrystallized from ethanol to give N-[4-(1-oxidopyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 162) (124 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[C:10](OCC)(=O)[CH:11]=[O:12].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:7]2[N:8]=[CH:10][C:11](=[O:12])[NH:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1ccnc(Cl)c1N
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1cnc2c(Cl)nccc2[nH]1
Temperature: -20 °C

Procedure:
A suspension 2-chloropyridine-3,4-diamine (2.5 g, 17.41 mmol) and a 50% solution of ethyl glyoxalate in toluene (3.45 mL, 17.41 mmol) in ethanol (34.8 mL) was stirred at reflux for 24 hours. The solution was cooled to −20° C. for 16 hours, and the resulting precipitate was collected by vacuum filtration and rinsed with ethanol. The crude product was purified via reverse-phase HPLC, eluting with 5-50% acetonitrile/0.1% trifluoroacetic acid in water/0.1% TFA, to afford the title compound (570 mg, 3.14 mmol). MS m/z=182 (M+H)+.