Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[C:23]([O:25]CC)=[O:24])=[N:19][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>O>[CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[C:23]([OH:25])=[O:24])=[N:19][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)OCC)nc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)O)nc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1.0 g sample of the crude ethyl 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoate from step 8 in 10 mL of water was treated with 3 mL of 10% aqueous sodium hydroxide and stirred at ambient temperature overnight. The reaction mixture was washed with 30 mL of ether and the pH adjusted to six with dilute hydrochloric acid. Purification by reverse phase chromatography (Waters Deltaprep-3000) using isocratic acetonitrile/water (28:72) (0.05% TFA) gave 5 mg of 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoic acid: NMR (D2O+NaO3S(CH2)3Si(CH3)3 ] δ0.80 (t, J=7 Hz, 3H), 0.86 (t, J=7 Hz, 3H), 1.19-1.33 (m, 4H), 1.54-1.68 (m, 4H), 2.65 (t, J=7 Hz, 2H), 2.82 (t, J=7 Hz, 2H), 5.43 (s, 2H), 7.45-7.59 (m, 5H), 7.64 (dd, J=8 and 2 Hz, 1H), 8.37-8.45 (m, 1H); MS (FAB) m/e (rel intensity) 393 (80), 375 (30), 212 (40), 182 (100); HRMS. Calc'd for M+Li: 399.2373. Found: 99.2374.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([NH:20][CH2:19][CH2:18][CH2:17][N:8]1[CH:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: O=C=NCc1ccccc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)NCc1ccccc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using benzyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+].CC(=C)C(OCCC[CH2:15][CH2:16][CH2:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35]CC)[CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20])=O.[I-].[Na+].O>CN(C)C=O>[C:1]([O:5][CH2:15][CH2:16][CH2:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:28][CH2:29][CH:30]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:32]2)[CH2:23][CH2:22]1)=[O:20])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)[O-]
Reactant: C=C(C)C(=O)OCCCCCCOC(=O)C1CCC(C2CCC(CCCCC)CC2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(=O)OCCCOC(=O)C1CCC(C2CCC(CCC)CC2)CC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of sodium acrylate (2.5 g, 13.4 mmol), 4′-propyl-bicyclohexyl-4-carboxylic acid 3-bromo-propyl ester (synthesis described for preferred example 1) (5.0 g, 13.4 mmol) and sodium iodide (2.5 g, 16.7 mmol) in dimethylformamide (150 ml) is stirred at 130° C. overnight. The mixture is cooled to room temperature, poured into water, and this is extracted twice with diethyl ether. The ethereal solution is washed with water and then dried over sodium sulphate. The solution is evaporated to dryness and purified by flash column chromatography using DCM/petrol (1/1) as eluant to give upon evaporation of the appropriate fractions a colourless oil.
Reaction SMILES: C1(C[O:8][C:9](=[O:22])[CH2:10][C:11](=[O:21])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)C=CC=CC=1>C1COCC1.[Pd]>[O:21]=[C:11]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:10][C:9]([OH:22])=[O:8]
Reactant: O=C(CC(=O)OCc1ccccc1)NCCc1ccccn1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CC(=O)NCCc1ccccn1

Procedure:
900 mg (3.03 mmol) 3-oxo-3-[[2-(2-pyridinyl)ethyl]amino]-propanoic acid phenylmethyl ester were dissolved in 25 ml THF and 15 mg palladium on charcoal (10%) were added. The reaction was kept under an atmosphere of hydrogen using a balloon for 10 hours. The mixture was filtered through dicalite. The solids were washed with THF and methanol. The combined filtrate was evaporated and dried under high vacuum. The crude product (300 mg) was used without further purification for the next reaction. 1H-NMR (CDCl3): 2.82–2.90 (m, 2H), 3.08 (s, 2H), 3.38–3.47 (m, 2H), 7.19–7.28 (m, 2H), 7.65–7.74 (m, 1H), 8.16–8.24 (m, br, 1H), 8.47–8.51 (m, H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N+:15]([O-])=[CH:14][C:13]1[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH3:27])[N:22]3[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:32]=C=O)=O.C(Cl)(Cl)Cl>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:32])[C:13]1[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@@H:23]([CH3:27])[N:22]3[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: C[C@H]1COCc2nc3c[n+]([O-])c4ccc(OCc5ccccc5)cc4c3n21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@@H]1COCc2nc3c(N)nc4ccc(OCc5ccccc5)cc4c3n21
Reaction time: 1 h
Yield: 67 %

Procedure:
(11S)-2-(Benzyloxy)-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (2.02 g, 5.59 mmol) and trichloroacetyl isocyanate (0.87 mL, 7.27 mmol) were dissolved in dichloromethane (50 mL) under an atmosphere of N2. After one hour, the reaction was quenched with a small amount of methanol, and the solvent was removed under reduced pressure. The resulting residue was suspended in methanol (50 mL) and treated with NaOMe (25% in MeOH, 8 mL) for 20 hours. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane and water, adjusting to pH 11 with NH4OH. The aqueous layer was extracted with dichloromethane (3×). The combined organic layers were then washed with brine and dried over Na2SO4, filtered, and concentrated to give a light-brown foam. Chromatography (SiO2, 0-20% CMA/CHCl3) gave (11R)-2-(benzyloxy)-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (1.35 g) as an off white solid, mp 100-120° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1S[C:15](=[O:24])[CH2:16][CH2:17][C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>CCOCC.C1COCC1>[C:18]1([CH2:17][CH2:16][C:15]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: O=C(CCC1=CCCCC1)Sc1ccccn1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCC1=CCCCC1)C1CCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
Cyclopentylmagnesium bromide (1.6 mL, 3.15 mmol, 2M soln in ether) was added to a cooled −78° C. solution of 3-Cyclohex-1-enyl-thiopropionic acid S-pyridin-2-yl ester (0.65 g, 2.63 mmol, from Step 3) dissolved in THF (10 mL). The reaction mixture was stirred for 45 min at −78° C. and then warmed up to rt. The reaction was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0% to 5% EtOAc in hexanes) to give the title compound as a clear oil (0.39 g, 72%). 1H NMR (CDCl3): δ 1.51-1.83 (br m, 12H), 1.91 (m, 2H), 1.97 (m, 2H), 2.20 (t, 2H, J=7.6 Hz), 2.54 (t, 2H, J=7.8 Hz), 2.87 (m, 1H), 5.39 (s, 1H).
Reaction SMILES: [SH:1][C@H:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[C@H:4]([C:20]([N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([S:1][C@H:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[C@H:4]([C:20]([N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH2:3]1)(=[O:37])[CH3:36]
Reactant: O=C(O)CN(CCc1ccccc1)C(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)S[C@@H]1C[C@@H](C(=O)N(CCc2ccccc2)CC(=O)O)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
A solution of 124 mg (0.2 mmol) (2S,4R)-{[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid in 3.2 ml pyridine were treated at 0° C. with 0.04 ml (0.4 mmol) acetyl chloride and stirred for 10 min at RT. The reaction was poured on ice water and extracted wit 1N HCl/EtOAc (3×). The organic phases were washed with aqueous 1 N HCl and 10% NaCl, dried over Na2SO4 and evaporated. Precipitation from CH2Cl2/Pentane (4° C.) gave 30 mg (28%) (2S,4R)-{[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid, mp: 190-193° C.; MS: 539 (M-H)−.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH:25]2[CH2:27][CH2:26]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1>>[CH:25]1([N:11]([CH:8]2[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH2:3][NH:28][CH:29]3[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]3)[CH2:10][CH2:9]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)(=[O:13])=[O:14])[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: C=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: O=C(CCNC1CCC(O)CC1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 150 °C

Procedure:
N-(1-Acryloyl-piperidin-4-yl)-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide (1) (125 mg, 0.31 mmol), trans-4-aminocyclohexanol (357 mg, 3.1 mmol) and ETOH (2.5 ml) were mixed together in a sealed tube and heated to 150° C. with microwave equipment for 30 min. After the reaction, the reaction mixture was evaporated in vacuum and the residue was purified by column chromatography on silica gel (CHCl3/MeOH/NH3 aq.=100/10/1) to afford the desired compound as free base, which was dissolved in AcOEt (2 ml), and treated with 4N—HCl in AcOEt (2 ml) solution. The resulting mixture was concentrated in vacuo, and dried under reduced pressure for 24 hours at 60° C. to afford the title compound 3 as a HCl-salt (colorless amorphous, 141 mg, yield 82%) LC: 100%. MS: m/z=517.88, 518.51 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:45][C:46](=[O:55])[C@H:47]([CH2:49][CH2:50][C:51]([O:53]C)=[O:52])[NH2:48]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:48][C@H:47]([C:46]([OH:45])=[O:55])[CH2:49][CH2:50][C:51]([OH:53])=[O:52])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)cc1

Procedure:
The product from Example 234B and L-glutamic acid dimethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.60-13.04 (br.s, 2 H), 8.94 (s, 1 H), 8.06 (d, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.95 (m, 6 H), 6.82 (d, 2 H), 4.21 (m, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (t, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.28 (m, 2 H), 2.19 (t, 2 H), 1.96 (m, 1 H), 1.60-1.82 (m, 5 H); MS (ESI+) m/z 718 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7](=[O:14])[CH:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:30]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:30][C:8]1[C:7](=[O:14])[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH:11]1[CH2:13][CH2:12]1
Reactant: BrBr
Reactant: CCCCc1nc(C2CC2)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C2CC2)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 4′-[(2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (5.22 g) in acetic acid (60 mL) was added bromine (1.39 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (5.4 g, 80%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:5]([NH:7][CH:8]1[C:37](=[O:38])[N:10]2[C:11]([C:21]([O:23]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:22])=[C:12]([C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][N:3]=[C:4]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:5]([NH:7][CH:8]1[C:37](=[O:38])[N:10]2[C:11]([C:21]([OH:23])=[O:22])=[C:12]([C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3nnc(C)s3)CS[C@H]12)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(c3nnc(C)s3)CS[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A mixture of 0.07 g of benzhydryl 7-(2-methoxyimino-2-phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate (obtained in Example 59), 2 ml of anisole and 4 ml of trifluoroacetic acid is stirred for 30 minutes at room temperature. After removal of the solvent under reduced pressure, the residue is triturated with the addition of absolute ether. The precipitates are filtered, and washed with ether to give 0.046 g of 7-(2-methoxyimino-2-phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylic acid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH:21][C:22]1[CH:26]=[CH:25][NH:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28]>C(Cl)Cl>[S:10]([O:21][C:22]1[CH:26]=[CH:25][NH:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28])([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1[nH]ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1[nH]ccc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (7.1 mL, 40.7 mmole) and then a solution of TsCl (6.46 gm, 33.9 mole) in dry DCM (20 mL) were added to an ice-cooled solution of methyl 3-hydroxy-1H-pyrrole-2-carboxylate (4.78 gm; 33.9 mmole) in dry DCM (80 mL) under a dry N2 atmosphere. After 2 hr, the reaction was removed from the bath and allowed to warm to RT. After 2 hr, this was washed with water, dried (Na2SO4), and the solvents removed to leave methyl 3-(tosyloxy)-1H-pyrrole-2-carboxylate (10 gm) as a solid. 1H NMR (CDCl3): 2.39 (s, 3H), 3.64 (s, 3H), 6.06 (m, 1H), 6.75 (m, 1H), 7.26 (m, 2H), 7.71 (m, 2H); MS: 311(M+H)+; HPLC Ret Time: 1.28 min (YMC Xterra S7 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](O)(=O)[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[SH:8].CO>ClC1C=CC=CC=1Cl>[NH:3]1[CH2:2][CH2:1][N:4]=[C:5]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[SH:8]
Reactant: O=C(O)c1ccccc1S
Reactant: NCCN
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: Sc1ccccc1C1=NCCN1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
21.6 mL (0.323 mol) of ethylenediamine was added to a suspension of 20.0 g (0.112 mol) of thiosalicylic acid in 200 mL of 1,2-dichlorobenzene, and refluxed under nitrogen for 4 h then cooled to ca. 60° C. and 50 mL of methanol was added. The solution was allowed to stand at 22° C. overnight and the resulting yellow crystalline solid was collected and washed with ether to give 10.6 g of pure product.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:29]
Reactant: CCOC(=O)CCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 75 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (25.0 g), dimethylformamide (200 ml), potassium carbonate (44.5 g) and ethyl 4-bromobutyrate (36.9 ml) were mixed at room temperature and stirred at 75° C. for 6 hr. The reaction mixture was cooled to room temperature, and the insoluble material was filtered off through celite. To the filtrate was added water (150 ml) and the mixture was extracted twice with ethyl acetate (100 ml, 50 ml). To the aqueous layer was added water (100 ml) again and the mixture was extracted twice with ethyl acetate (50 ml). To the combined organic layer was added n-hexane (100 ml), and the mixture was washed 3 times with water (100 ml) and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate-5/1 to 1/1) to give the title compound (33.4 g, 84%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([NH:39][C@@H:40]([C:42](O)=[O:43])[CH3:41])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[NH2:39][C@H:40]([CH3:41])[C:42]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:4]2[S:5][C:6]3[C:11]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[N:10][C:9]([C:18]4[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=4)=[N:8][C:7]=3[C:3]=2[CH3:2])[CH2:27][CH2:28]1)=[O:43]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCN(C(=O)[C@@H](C)N)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 39 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 60 mg Boc-D-Alanine via General Procedure B, treated with TFA and purified via reverse phase HPLC to yield 33.7 mg of 353 after reverse phase HPLC purification. MS (Q1) 498.3 (M)+
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:27]#[N:28])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24]C3)[CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:29])(OC)=O.CS(C)=O.[Cl-].[Na+]>O>[C:27]([C:9]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:26]3[CH2:24][CH2:25]3)[CH:12]=2)[CH2:10][CH2:5][C:6](=[O:29])[CH2:7][CH2:8]1)#[N:28]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(OC(F)F)c(OCC3CC3)c2)CCC(=O)CC1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one (0.5 g, 1.27 mmol), dimethyl sulfoxide (10 mL), water (1 mL) and sodium chloride (0.5 g) under an argon atmosphere was heated at 145°-150° C. for 4.5 h. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water, extracted twice with ethyl acetate,the organic layer was washed twice with water and once with brine, was dried (sodium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 20-25% ethyl acetate/hexanes,and the resultant solid was triturated with ether/hexane and then with cold ether to provide a solid (0.22 g, 51.6%): m.p. 85.5-86.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@H:20]2[CH2:28][N:27]3[C@@H:22]([CH2:23][O:24][CH2:25][CH2:26]3)[CH2:21]2)=[C:15]([N+:29]([O-])=O)[CH:14]=1.C(N(CC)CC)C.Cl[C:45](Cl)([O:47]C(=O)OC(Cl)(Cl)Cl)Cl>[Pt].O1CCCC1.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@H:20]3[CH2:28][N:27]4[C@@H:22]([CH2:23][O:24][CH2:25][CH2:26]4)[CH2:21]3)[C:45](=[O:47])[NH:29][C:15]=2[CH:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(/C=C2\c3ccccc3COc3cc(F)ccc32)ccc1N[C@@H]1C[C@@H]2COCCN2C1
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(/C=C3\c4ccccc4COc4cc(F)ccc43)ccc2n1[C@@H]1C[C@@H]2COCCN2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
Hydrogenate a mixture of (E)-[4-(3-fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-((7R,8aR)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (52 g, 0.107 mol), triethylamine (33 mL, 0.237 mol) and 5% platinum on carbon (18 g) in tetrahydrofuran (450 mL) at room temperature at 50 psi for 2 h. Filter off the catalyst, rinse with tetrahydrofuran, and concentrate to obtain a brown foam. Dissolve the foam in anhydrous tetrahydrofuran (500 mL) and cool in an ice bath. Add triphosgene (31.5 g, 0.106 mol) in tetrahydrofuran (450 mL) dropwise over 30 min and stir at room temperature for 16 h. Concentrate the solution, dissolve in 5% methanol in dichloromethane and purify through a short silica gel plug. Concentrate to obtain a brown solid. Suspend the solid in saturated sodium bicarbonate (1.5 L) and stir on the rotary evaporator for one hour. Filter and dry in vacuo. Dissolve in warm 1:1 methanol/dichloromethane (approximately 6 L) and treat with poly (4-vinylpyridine) 2% cross-linked resin (170 g). Stir the slurry for 30 min and filter through diatomaceous earth. Concentrate the filtrate to approximately 1.5 L volume and collect the resulting solids by filtration. Dry at 80° C./20 mm Hg overnight to obtain the title compound as a white solid (38.1 g, 74%). [α]D20−20.5 (c=1.0 in DMSO). 1H NMR (400 MHz, DMSO-d6) δ 1.48 (m, 1H), 2.02 (m, 1H), 2.19 (m, 2H), 2.52 (m, 1H), 2.91 (d, 1H), 3.03 (d, 1H), 3.25 (t, 1H), 3.50 (t, 1H), 3.79 (d, 1H), 3.88 (d, 1H), 4.95 (m, 1H), 5.03 (broad s, 1H), 5.60 (broad s, 1H), 6.59 (m, 2H), 6.78 (m, 2H), 6.97 (s, 1H), 7.02 (d, 1H), 7.25 (t, 1H), 7.38 (t, 1H), 7.48-7.61 (m, 3H), 10.72 (s, 1H, NH). LC-MS m/z 484.0 [M+H]+.