Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.O>C(Cl)Cl>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:9](=[O:10])[O:11][CH2:12][CH3:13])=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 1.5 h
Yield: 88 %

Procedure:
0.14 ml of triethylamine and 0.08 ml of ethyl chloroformate were added to a solution of 250 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in Example 3(b) above] in 5 ml of methylene chloride cooled in an ice-water bath, and the resulting mixture was then stirred for 1.5 hours. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate to give 284.8 mg (yield 88%) of the title compound as a solid having a melting point of 149°-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CCN(CC)CC>C(Cl)Cl>[CH:26]1([NH:31][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([OH:16])([CH3:15])[CH3:14])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)O
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NC1CCCC1)C(C)(C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a mixture of (R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid (0.5 g, 2.144 mmol), HATU (0.978 g, 2.57 mmol) and cyclopentanamine (0.423 mL, 4.29 mmol) in DCM (10 mL) was added Et3N (0.598 mL, 4.29 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, concentrated, and purified by silica column chromatography (MeOH/DCM, 0-10%) to afford the title compound (0.6 g, 93%).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([CH2:9][O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:4]1.CCN(S(F)(F)[F:23])CC>C(Cl)Cl>[NH3:6].[F:23][CH2:2][C@@H:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([CH2:9][O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:4]1
Reactant: CN1CC(CO)C[C@H]1COc1cccnc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN1C[C@@H](CF)C[C@H]1COc1cccnc1
Product: N
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A 1.57 g (7.1 mmol) sample of 3-((4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine, prepared as described in Example 48b above, was dissolved in 40 mL of methylene chloride, and the solution was cooled to -78° C. To this solution was added 2.80 mL (21.2 mmol) of DAST, then the solution was stirred at -35° C. for 1.5 hours. The reaction mixture was warmed to room temperature, and the reaction was quenched by the addition of satd NaHCO3. The mixture was extracted with chloroform, the solvent was removed, and the residue was purified on a silica gel column, eluting with 100:2 chloroform:methanol to 10:1:0.02 chloroform:methanol:ammonia, to give 120 mg of the title compound.
Reaction SMILES: CC(C)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH:13][C:14]([CH2:16][O:17][N:18]=[C:19]([C:43]1[N:44]=[C:45]([NH:48]C=O)[S:46][CH:47]=1)[C:20]([NH:22][CH:23]1[C:41](=[O:42])[N:25]2[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][S:31][C:32]3[N:36]([CH3:37])[N:35]=[N:34][N:33]=3)[CH2:28][S:29][C@H:24]12)=[O:21])=[O:15].Cl>CO>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH:13][C:14]([CH2:16][O:17][N:18]=[C:19]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:20]([NH:22][CH:23]1[C:41](=[O:42])[N:25]2[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][S:31][C:32]3[N:36]([CH3:37])[N:35]=[N:34][N:33]=3)[CH2:28][S:29][C@H:24]12)=[O:21])=[O:15]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3cc(Cl)ccc3O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3cc(Cl)ccc3O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a mixture of acetone (1 ml.), methanol (4 ml.) and 7-[2-{N-(2-hydroxy-5-chlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.55 g.) was added conc. hydrochloric acid (0.11 ml.) followed by stirring for 3 hours at room temperature. The reaction mixture was concentrated and then to the residue were added water (3 ml.) and an aqueous solution of sodium bicarbonate whereby the pH was adjusted to about 2. The resulting mixture was stirred at room temperature and the precipitates were collected by filtration, washed with water and then dried to give the title compound (0.40 g.), mp. 165° to 175° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23].[C:25]([O:29][C:30](=[O:36])[NH:31][CH2:32][CH2:33][CH2:34]Br)([CH3:28])([CH3:27])[CH3:26]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:36])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)CC1Cc2ccc(O)cc2N(Cc2ccccc2)C1=O
Solvent: CC(=O)O
Product: COC(=O)CC1Cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2N(Cc2ccccc2)C1=O

Procedure:
The title compound is prepared using the procedure of Example 75 and (1-benzyl-7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid and (3-bromopropyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: ClCCN1CCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 1-(2-chloroethyl)-pyrrolidine
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH:11](OCC)(OCC)OCC.[N:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>CCCCCC>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[CH:11][NH:27][C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)[C:4](=[O:9])[O:3]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccncc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCCCCC
Product: CC1(C)OC(=O)C(=CNc2ccncc2)C(=O)O1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
In a dried 2-necked RBF equipped with reflux condenser and inert atmosphere, 2,2-dimethyl-1,3-dioxane-4,6-dione (2.33 g, 16 mmol) was dissolved in triethyl orthoformate (16 ml, 97 mmol) and the mixture was stirred at 100° C. under nitrogen for 1.5 h. On complete consumption of starting material (tic), pyridin-4-amine (1.5 g, 16 mmol) was added and heating continued for 4.5 h. The reaction mixture was cooled down to RT and poured into hexane (50 mL). The solid was filtered off and washed with hexane to afford 2,2-dimethyl-5-((pyridin-4-ylamino)methylene)-1,3-dioxane-4,6-dione as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=O.Cl.[NH2:20][OH:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[N:20][OH:21]
Reactant: NO
Reactant: O=Cc1c(Cl)cc(-c2ccc(O)c(F)c2)cc1Cl
Agent: Cl
Product: ON=Cc1c(Cl)cc(-c2ccc(O)c(F)c2)cc1Cl

Procedure:
The title compound was prepared by reacting 3,5-dichloro-3′-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbaldehyde (290 mg, mmol) with hydroxylamine hydrochloride (140 mg, 1.27 mmol) according to Method F to yield 260 mg (85%) of a white solid: mp 185-190° C.; 1H NMR (DMSO-d6): δ 7.03 (1H, t, J=8.86 Hz), 7.46-7.49 (1H, m), 7.68 (1H, dd, J=12.74 Hz, J=2.26 Hz), 7.82 (2H, s), 8.25 (1H, s), 10.24 (1H, s), 11.80 (1H, s); MS (ESI) m/z 298/300/302 (M−H)−, 300/302/304 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:32]([N:39]([CH2:46][C@H:47]([OH:51])[CH2:48][O:49][CH3:50])[CH2:40][C@H:41](O)[CH2:42][O:43][CH3:44])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>O1CCCC1>[CH2:32]([N:39]1[CH2:40][C@H:41]([CH2:42][O:43][CH3:44])[O:51][C@H:47]([CH2:48][O:49][CH3:50])[CH2:46]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC[C@@H](O)CN(Cc1ccccc1)C[C@H](O)COC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC[C@@H]1CN(Cc2ccccc2)C[C@H](COC)O1
Temperature: 0 °C
Reaction time: 5 h
Yield: 38.6 %

Procedure:
A mixture of triphenylphosphine (10.2 g), diethyl azodicarboxylate (6.12 ml), and (2S)-1-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-3-methoxypropan-2-ol (7.34 g) in tetrahydrofuran (70 ml) was stirred at 0° C. for 5 hours. To the mixture was added successively triphenylphosphine (2.04 g) and diethyl azodicarboxylate (1.2 ml), and the mixture was stirred at 0° C. for 3 hours. The mixture was poured into water and extracted with dichloromethane (×3). The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. Isopropyl ether (50 ml) was added to the residue and stirred at room temperature for 30 minutes. The insoluble precipitate was filtered off, and the solution was evaporated and purified twice with column chromatography (1st: silica gel 800 ml, ethyl acetate:isopropyl ether=2:8–3:7) (2nd: silica gel 300 ml, ethyl acetate:isopropyl ether 3:97–10.90) to give 4-benzyl-cis-2,6-dimethoxymethylmorpholine (2.65 g) as an oil.
Reaction SMILES: [C:1](=[O:9])([O:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8])[NH2:2].[C:10](Cl)(Cl)=[O:11]>CCCCCCCCCCCCCCCCCCCNC=O.ClC1C=CC=CC=1>[Cl:8][CH2:7][CH2:6][CH2:5][CH2:4][O:3][C:1]([N:2]=[C:10]=[O:11])=[O:9]
Reactant: NC(=O)OCCCCCl
Reactant: O=C(Cl)Cl
Agent: CCCCCCCCCCCCCCCCCCCNC=O
Solvent: Clc1ccccc1
Product: O=C=NC(=O)OCCCCCl
Reaction time: 6 h
Yield: 44 %

Procedure:
45 5 g of δ-chlorobutyl carbamate were initially introduced as a melt and 63 g of phosgene were passed into the melt at 80° C. within 6 hours. 150 g of chlorobenzene and 0.36 g (=0.4 mol %) of methylstearylformamide were then added and a further 159 g of phosgene were passed into the mixture at 130° C. over a further 16 hours. Excess phosgene was subsequently driven out using nitrogen. 23.7 g of δ-chlorobutyloxycarbonyl isocyanate having a boiling point of 86° to 109° C. at 20 mbar were obtained on subsequent distillation, corresponding to a yield of 44% of theory.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1/[CH:10]=[C:11]1/[C:12](=[O:24])[C:13]2[C:18]([CH2:19]/1)=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH3:23])[CH:14]=2)(=[O:3])[CH3:2].[CH2:25]([Br:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br-:32].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=[CH:8][C:9]=1/[CH:10]=[C:11]1/[C:12](=[O:24])[C:13]2[C:18]([CH2:19]/1)=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH3:23])[CH:14]=2)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1C(C)=O)C2
Product: COc1cc2c(cc1OC)C(=O)/C(=C/c1cc[n+](Cc3ccccc3)cc1C(C)=O)C2
Product: [Br-]

Procedure:
The title compound 149 is prepared according to the procedure reported in Example 38.1 with compound 97 (83 mg, 0.26 mmol) and benzyl bromide (64 μL, 0.52 mmol) as reactants. White solid. (Yield 101.1 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(C=O)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
A solution of 6-methoxy-3-pyridine carboxaldehyde (100 mg, 0.73 mmol) in ethanol (2 mL) and acetic acid (0.2 mL) at room temperature was treated with tert-butyl-1-piperazine carboxylate (2.5 eq, 1.82 mmol, 339 mg) and stirred for 5 minutes. Sodium cyanoborohydride (0.95 eq, 0.69 mmol, 44 mg) was added portionwise and the reaction then stirred for 16 h. Concentration in vacuo and preparative tlc purification (EtOAc) gave the product (168 mg, 75%) as a colourless oil; δH (500 MHz, CDCl3) 1.47 (s, 9H, C(CH3)3), 2.00 (s, br, 2H, piperazine NCH2), 2.39 (t, J=4.7 Hz, 2H, piperazine NCH2), 3.43 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 3.45 (s, 2H, CH2), 3.94 (s, 3H, OCH3), 6.73 (d, J=8.4 Hz, 1H, methoxypyridine H-5), 7.57 (dd, J=8.5, 2.4 Hz, 1H, methoxypyridine H-4), 8.05 (d, br, J=2.3 Hz, 1H, methoxypyridine H-2);
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([N:15]([CH3:23])[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])[CH2:7][C@@H:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1.[NH:28]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[C:31]=2[CH:30]=[CH:29]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[NH:28]1[C:36]2[C:31](=[C:32]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([N:15]([CH3:23])[CH2:16][CH:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:14])[CH2:7][C@@H:6]5[CH2:24][O:25][CH2:26][CH2:27][N:5]5[C:4]=4[N:3]=3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CN(CC1CCOCC1)C(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
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: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CC1CCOCC1)C(=O)CN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 120 °C
Yield: 43.6 %

Procedure:
A mixture of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x79, 70 mg, 0.177 mmol), indole-4-boronic acid (42.7 mg, 0.265 mmol), tetrakis(triphenylphosphine)palladium(0) (20.43 mg, 0.018 mmol), and sodium carbonate (37.5 mg, 0.354 mmol) in 1,4-dioxane (0.7 mL) and water (0.35 mL) was heated to 120° C. for 1 hour in a microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica-NH, gradient 0-10% MeOH/CHCl3) to afford the title compound as an off-white solid (36.8 mg, 43.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.61 (m, 4 H), 1.78-1.97 (m, 1 H), 2.80-3.09 (m, 4 H), 3.12-3.38 (m, 7 H), 3.58 (t, J=9.98 Hz, 2 H), 3.78-4.16 (m, 5 H), 4.41-4.60 (m, 2 H), 7.11 (t, J=7.71 Hz, 1 H), 7.26-7.64 (m, 4 H), 7.86-7.95 (m, 1 H), 11.11 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C26H32N6O3, 477.26; found 477.3.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:34]C(=O)C1C=CC=CC=1)=[N:21]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH2:34])=[N:21]2
Reactant: CC(C)C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(C)C[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 60 °C

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (3.0 μL, 20 μmol) was added to a solution of N-[(4aR,6S,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylpropyl)-4,4a, 5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C29) (10.5 mg, 23.6 μmol) in methanol (0.4 mL) and the reaction mixture was heated at 60° C. for 18 hours in a sealed vial. Solvent was removed under a stream of nitrogen, and the residue was partitioned between water (3 mL) and ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (5 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification was carried out via reversed phase high-performance liquid chromatography (Column: Waters XBridge C18, 5 μm; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 30% to 100% B). Yield: 4.2 mg, 12 μmol, 51%. LCMS m/z 341.1 [M+H+]. 1H NMR (600 MHz, DMSO-d6) δ 7.31-7.36 (m, 1H), 7.15-7.20 (m, 1H), 7.08 (ddd, J=9, 8, 2 Hz, 1H), 3.86 (dd, J=10.5, 1.8 Hz, 1H), 3.54 (d, J=10.5 Hz, 1H), 3.50-3.56 (m, 1H), 2.62-2.73 (m, 3H), 1.71-1.79 (m, 1H), 1.52-1.60 (m, 1H), 1.45-1.50 (m, 1H), 1.40 (ddd, J=14, 8, 6 Hz, 1H), 1.21 (ddd, J=14, 8, 4.5 Hz, 1H), 0.89 (d, J=6.1 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]4[CH:37]5[CH:33]([NH:34][C:35](=[O:38])[NH:36]5)[CH2:32][S:31]4)=[C:20]([O:40]CC4C=CC=CC=4)[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]4[CH:37]5[CH:33]([NH:34][C:35](=[O:38])[NH:36]5)[CH2:32][S:31]4)=[C:20]([OH:40])[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1O
Yield: 63 %

Procedure:
{3-Benzyloxy-4-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-phenyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (389) (0.28 g, 0.422 mmol) was dissolved in TFA (2 mL) and thioanisole (0.4 mL) was added. The mixture was shaken at room temperature in a Teflon septum capped 40 mL I-Chem vial for 3 h. LC-MS indicated complete de-benzylation at this point. The mixture was diluted with water (15 mL) and a pink/orange precipitate formed. Collection by filtration under reduced pressure followed by rinsing with water followed by drying under high vacuum for 16 h gave the desired product (390) as a pink/orange powder (0.152 g, 0.266 mmol, 63% yield). LC-MS (ESI): (exact mass: 572.21) m/e=573.1 [M+1]+.
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:17][CH2:16][C:15]([N:24]([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=O)(C)(C)C.CO.C(Cl)(Cl)[Cl:30]>CO>[ClH:4].[ClH:30].[CH3:25][N:24]([CH3:26])[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]1
Reactant: ClC(Cl)Cl
Reactant: CN(C)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCNCC1
Product: Cl

Procedure:
10 equivalents of acetyl chloride were added to a solution of tert-butyloxycarbonyl-4-(dimethylamino)-4-phenylpiperidine in methanol at 0° C. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure and the product obtained in the form of a solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([N:21]=[C:22]([N:25]([CH3:34])[N:26]=CC1C=CC=CC=1)SC)#[N:20].Cl>CC(C)=O>[CH3:34][N:25]1[C:22]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[N:21][C:19]([NH2:20])=[N:26]1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Solvent: CC(C)=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 28.5 %

Procedure:
3-[3-[1-Piperidinylmethyl]phenoxy]propanamine (2.48 g) and N-cyano-1-methyl-2-(phenylmethylene) hydrazine carboximidothioic acid, methyl ester (2.32 g) were heated at 70° under water-pump vacuum for 4 hr. Acetone was added and the solution was treated with dilute hydrochloric acid for 1 hr, washed with ether, basified and extracted with ethyl acetate. Evaporation of the ethyl acetate extracts gave an oil which crystallised from toluene/ether to give the title compound as a white solid (0.98 g) m.p. 94°-5°. TLC silica, methanol/0.88 ammonia 80:1, Rf 0.5.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1COCC1>[C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])(=[O:14])[CH3:13]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc([N+](=O)[O-])c1C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
84 g of 2-methyl-3-nitroaniline is dissolved in 550 ml of THF. 53 ml of acetic anhydride is slowly added dropwise and the mixture is then stirred at 70° C. After about 1 hour, THF is distilled off and the residue is combined with 250 ml of petroleum ether. The solid precipitate is filtered off and dried at 50° C. 106 g of N-acetyl-2-methyl-3-nitroaniline is obtained as a light brown powder.
Reaction SMILES: CN[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]([O:14]CC2C=CC=CC=2)=[O:13])=[CH:5][CH:4]=1.[H][H].C[CH2:26][O:27]C(C)=O.CO>[Pd]>[CH3:26][O:27][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CNc1ccc(NC(=O)CC(=O)OCc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NC(=O)CC(=O)O)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of Intermediate 6A (14.4 g, 4.8 mmol) in 10:1 EtOAc/MeOH (220 mL) was added 10% Pd/C (250 mg). The reaction mixture was stirred vigorously under an atmosphere of hydrogen (40 psi) for 2 h. More 10% Pd/C (250 mg) was added and the reaction was stirred under 50 psi hydrogen for another 1 h. Additional 10% Pd/C (500 mg) was added and the reaction was stirred under 50 psi hydrogen for an additional 1 h. The reaction was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to yield Intermediate 6B (11.1 g, 96%) as an off-white solid. LCMS Anal. Calc'd for C10H11NO4 209.20, found [M+H] 210.1.