Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:50]/[O:51][CH3:52])/[C:15]([NH:17][C@@H:18]2[C:48](=[O:49])[N:20]3[C:21]([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:33])=[C:22]([S:25][CH2:26][C:27]4[S:31][N:30]=[N:29][CH:28]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.C(O)(C)C>C1(OC)C=CC=CC=1.ClCCl>[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:50]/[O:51][CH3:52])/[C:15]([NH:17][C@@H:18]2[C:48](=[O:49])[N:20]3[C:21]([C:32]([OH:34])=[O:33])=[C:22]([S:25][CH2:26][C:27]4[S:31][N:30]=[N:29][CH:28]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cnns3)CS[C@H]12)c1csc(N)n1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CC(C)O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cnns3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
Under nitrogen atmosphere, trifluoroacetic acid (2.0 ml) was added dropwise to a solution of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-[(1,2,3-thiadiazol-5-yl)methylthio]-3-cephem-4-carboxylate (1.02 g) in anisole (1.0 ml) and dichloromethane (3.0 ml) under ice cooling. The mixture was stirred for 1 hour at room temperature, and then poured into 150 ml of isopropanol. The resulting precipitate was collected by filtration and treated on HP-20 (eluent: water-methanol) to afford 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-[(1,2,3-thiadiazol-5-yl)methylthio]-3-cephem-4-carboxylic acid (193.3 mg).
Reaction SMILES: FC1C=CC(CBr)=CC=1.[CH3:10][S:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32](=[O:33])[NH:31][N:30]=[CH:29]2)[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH2:18][C:17]3[CH:20]=[CH:21][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:15][CH:16]=3)[N:30]=[CH:29]2)[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Agent: Fc1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(S(C)(=O)=O)cc3)c2=O)cc1C
Yield: 81 %

Procedure:
Following the procedure as described in Example 29, making variations as required to replace 4-fluorobenzyl bromide with 4-methylsulfonylbenzyl bromide to react with ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a yellowish solid in 81% yield: 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=7.9 Hz, 2H), 7.76 (s, 1H), 7.59 (d, J=7.9 Hz, 2H), 6.95 (s, 1H), 5.10 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 3.04 (s, 3H), 2.55 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 444.3 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][S:33][CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: C1CSCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCSCC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with thiomorpholine (0.020 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(thiomorpholinomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]1.Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1.CCN(CC)CC>COCCOC>[O-:26][N+:15]1[C:16]2[CH:25]=[C:24]3[C:20](=[CH:19][C:17]=2[N:18]=[C:13]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]2)[N:14]=1)[CH2:21][CH2:22][CH2:23]3
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: N#CC1CCN(CCCN)C1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: N#CC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Yield: 78.1 %

Procedure:
1-(3-Aminopropyl)-3-pyrrolidinecarbonitrile (302) (0.36 g, 2.4 mmol) was added to a stirred solution of chloride 21 (402 mg, 1.8 mmol) and Et3N (0.76 mL, 5.4 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 56 (476 mg, 78%) as a yellow solid: mp (EtOAc/pet. ether) 111-112° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.72 (br t, J=5.3 Hz, 1H, NH), 3.58 (q, J=6.4 Hz, 2H, CH2N), 2.95-3.07 (m, 6H, H-6, H-8, CH2N), 2.73-2.80 (m, 1H, CHCN), 2.55-2.68 (m, 4H, 2×CH2), 2.23-2.32 (m, 1H, CH2), 2.10-2.18 (m, 3H, CH2, H-7), 1.85 (p, J=6.7 Hz, 2H, CH2); 13C NMR δ 158.7, 154.6, 148.7, 143.3, 129.8, 122.1, 120.6, 114.6, 57.4, 53.3, 52.9, 40.2, 33.1, 32.3, 29.2, 27.7, 26.3, 25.7. Anal. calcd for C18H22N6O: C, 63.9; H, 6.6; N, 24.8. Found: C, 64.0; H, 6.4; N, 24.8%.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.C(OC([NH:66][C@H:67]([C:71](O)=[O:72])[C@@H:68]([CH3:70])[OH:69])=O)(C)(C)C.[OH-].[Na+]>C1COCC1.CC(=O)OCC>[NH2:66][C@@H:67]([C@H:68]([OH:69])[CH3:70])[C:71]([NH:25][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)[N:15]=2)[CH2:20][CH2:21]1)=[O:72]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H](N)C(=O)NC1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
190 mg (0.47 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine were dissolved in 5 ml of THF, and 86 mg (0.56 mmol) of 1-hydroxybenzotriazole hydrate, 239 μl (1.40 mmol) of N-ethyldiisopropylamine, 108 mg (0.56 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 113 mg (0.56 mmol) of N-(tert-butoxycarbonyl)-L-threonine were added. The mixture was stirred at room temperature overnight, dissolved in EA and 1 N NaOH and shaken. The organic phase was washed with water, dried over sodium sulfate, filtered and evaporated. The protecting group was cleaved off as already described using HCl in dioxane. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=2)[C:5]=1[O:19][CH2:20][C@H:21]1[CH2:23][O:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:19][CH2:20][C@H:21]([CH2:23][OH:22])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:24]
Reactant: COC(=O)c1cccc(Nc2ccc(OC)cn2)c1OC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1OC[C@H](CO)N2c1ccc(OC)cn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of (R)-methyl-3-(5-methoxypyridin-2-ylamino)-2-(oxiran-2-ylmethoxy)benzoate 0.53 g (1.6 mmol) of step 5 in dimethylformamide 5 mL was added K2CO3 0.28 g (2.0 mmol), followed by stirring at 100° C. for 5 hrs. The reaction mixture is cooled to room temperature, concentrated in a vacuum, diluted with ethylacetate, and washed with distilled water and a saturated NaCl solution. After drying over magnesium sulfate and concentration in a vacuum, purification by column chromatography (developing solvent: ethylacetate/hexane=1/1) afforded 0.50 g of the title compound (yield 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:7]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[C:32]([NH2:34])[C:31]([C:35]#[N:36])=[CH:30][C:29]=2[O:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:42][N:43]([CH:45](OC)OC)[CH3:44]>CCOCC>[C:4]([C:3]1[CH:6]=[C:7]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[C:32](/[N:34]=[CH:42]/[N:43]([CH3:45])[CH3:44])[C:31]([C:35]#[N:36])=[CH:30][C:29]=2[O:37][CH2:38][CH2:39][O:40][CH3:41])[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]=1/[N:1]=[CH:42]/[N:43]([CH3:45])[CH3:44])#[N:5]
Reactant: COCCOc1cc(C#N)c(N)cc1OCCOCCOCCOCCOc1cc(C#N)c(N)cc1OCCOC
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Product: COCCOc1cc(/N=C/N(C)C)c(C#N)cc1OCCOCCOCCOCCOc1cc(/N=C/N(C)C)c(C#N)cc1OCCOC

Procedure:
2-Amino-5-(2-(2-(2-(2-(5-amino-4-cyano-2-(2-methoxyethoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-(2-methoxyethoxy)benzonitrile (0.18 g) was added to DMF-DMA (3 mL), the resulting mixture was heated to reflux overnight under N2 atmospheres. After reaction finished, the mixture was diluted with Et2O (30 mL) and solid was collected. The solid was washed with Et2O and air-dried to give (E)-N′-(2-cyano-4-(2-(2-(2-(2-(4-cyano-5-((E)-((dimethylamino)methylene)amino)-2-(2-methoxyethoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformimidamide (0.2 g) as a yellow solid, which was used in next step directly without any purification.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][N:12]3[CH2:16][C:15]4([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[O:14][C:13]3=[O:22])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:25]=O>C(O)=O>[CH3:25][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:16][C:15]4([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[O:14][C:13]3=[O:22])=[CH:23][CH:24]=2)[CH2:5][CH2:6]1
Reactant: O=C1OC2(CCCCC2)CN1Cc1ccc(C2=CCNCC2)cc1
Reactant: C=O
Solvent: O=CO
Product: CN1CC=C(c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)CC1
Temperature: 100 °C
Yield: 78 %

Procedure:
3-[4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-benzyl]-1-oxa-3-aza-spiro[4.5]decan-2-one (31 mg, 0.095 mmol), formaldehyde (1.5 mL) and formic acid (1.5 mL) were mixed and heated at 100° C. for 2 hours. The reaction mixture was concentrated; the residue was dissolved in DCM (2 mL) and neutralized by adding saturated NaHCO3. The aqueous phase was extracted with DCM (2×3 mL). The combined organic phase was dried over sodium sulfate and concentrated in vacuo. The crude residue was purified on silica gel eluting with 2M NH3 in methanol/DCM (4: 96) to give the product as off-white solid (25 mg, 78%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.39 (d, 2H), 7.23 (d, 2H), 6.09 (br, 1H), 4.41 (s, 2H), 3.13 (br, 2H), 3.09 (s, 2H), 2.7 (m, 2H), 2.59 (br, 2H), 2.42 (s, 3H), 1.78 (m, 4H), 1.54 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 45.8 %

Procedure:
Following the procedure of Example 1(10), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiprazine were reacted to yield the title compound as a slightly-brown crystalline powder (yield: 45.8%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Cc1cnc(Br)cn1
Product: Cc1cnc(-c2cc(C)c(Br)c(C)c2)cn1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-5-methyl-pyrazine following a procedure analogous to that described in Step 1 of Intermediate 56. Mass spectrum (ESI+): m/z=277/279 (Br) [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C1(CN2CCC3(CCCC3)C2=O)C=CC=CC=1>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:10]1[CH2:11][CH2:12][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]1=[O:13]
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: BrCCCCBr
Agent: O=C1N(Cc2ccccc2)CCC12CCCC2
Solvent: C1CCOC1
Product: O=C1C(CCCCBr)CCN1Cc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 1-(phenylmethyl)-2-pyrrolidinone (0.47 g, 2.7 mmol) in THF (10 ml) at −78° C. was added lithium hexamethyldisilylazine (2.8 ml, 2.7 mmol, 1M solution) over 5 min. After 15 min 1,4-dibromobutane (0.32 ml, 2.7 mmol) was added and the solution allowed to attain ambient temperature over 2 h then stirred for a further 18 h. The solution was separated between ethyl acetate and water and the organics isolated, dried and concentrated. Chromatography over silica (20 g SPE) eluting with cyclohexane then DCM and finally ether provided a clear oil which was a 1:1 mixture of the title compound and 2-(phenylmethyl)-2-azaspiro[4.4]nonan-1-one (0.17 g). This was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]=4[F:30])[C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]=4[F:30])[C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150.0 mg (0.35 mmol) of tert-butyl(+/−)-cyclopentyl{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetate were initially charged in 300 μl of dichloromethane, and 515 μl of trifluoroacetic acid were added. The mixture was stirred at RT for 1 h. The reaction mixture was then concentrated on a rotary evaporator, and the residue was dried under high vacuum. Acetonitrile was added to the product, and the precipitated solid was triturated and then filtered off with suction. This gave 112.0 mg (86.1% of theory) of the target compound.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[C:8](Cl)(=[O:10])[CH3:9]>>[C:8]([P:1](=[O:2])([O:6][CH3:7])[O:4][CH3:5])(=[O:10])[CH3:9]
Reactant: COP(OC)OC
Reactant: CC(=O)Cl
Product: COP(=O)(OC)C(C)=O
Temperature: 25 °C
Yield: 44 %

Procedure:
Trimethyl phosphite (57.1 g, 0.46 mol) is added dropwise to an ice cold solution of acetyl chloride (36.2, 0.26 nol) at a rate that the internal temperature did not rise above 5° C. The ice bath is removed and the solution warmed to room temperature and then heated to 100° C. for 1 hour. The solution is then vacuum distilled through a 12-inch Vigeraux column to give 30.87 g, 44% of a clear liquid with bp 57°-60° C. at 0.5 mm. H and C nmr are consistent with the assigned structure. This procedure is adapted from the published method of McConnell, R. L., Coover, H. W.,Jr. J. Am. Chem. Soc., 1956, 78, 4450-4452. ##STR20##
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[O-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: COc1ccccc1C1=CCN(Cc2ccccc2)CC1
Temperature: 160 °C
Yield: 47.3 %

Procedure:
1-Benzyl-4-(2-methoxyphenyl)piperidin-4-ol (4.5 g, 15.15 mmol) was mixed with anhydrous potassium bisulphate (8.0 g, 58.56 mmol) and heated to 160° C. under vacuum at 10 mm Hg for 0.5 h. The flask was cooled, the contents dissolved in water and the solution was saturated with sodium carbonate and extracted with ether (2×1100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:1) to furnish 1-benzyl-4-(2-methoxyphenyl)-1,2,3,6-tetrahydropyridine (2.0 g, 45%). 1H NMR (200 MHz, CDCl3): δ 2.551-2.573 (m, 2H), 2.67-2.71 (m, 2H), 3.16-3.19 (brs, 2H), 3.66 (s, 2H), 3.79 (s, 3H), 5.76-5.78 (brs, 1H), 6.83-6.92 (m, 2H), 7.15-7.41 (m, 7H); m/e=279 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>C(Cl)Cl>[CH:27]([O:26][C:24]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)=[O:25])([CH3:29])[CH3:28]
Reactant: NCCCCSc1cccc2nccn12
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NCCCCSc1cccc2nccn12
Yield: 41.9 %

Procedure:
To 5-(4-amino)butylthioimidazo[1,2-a]pyridine (370 mg, 1.67 mmoles) and triethylamine (0.35 ml, 2.51 mmoles) in methylene chloride (20 ml) was added isopropyl chloroformate (0.25 g, 2.04 mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was washed in turn with aqueous saturated sodium bicarbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 215 mg of the desired product (41.8%, light tan oily product).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][OH:43]>>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][O:43][C:21]([C@@:19]12[CH2:18][N:17]([S:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2)=[O:22]
Reactant: CN(C)CCO
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Product: CN(C)CCOC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 48c using (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride and 2-dimethylamino ethanol. LCMS (Method F): 610 (M+H)+, Retention time 3.4 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][Cl:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)C[N:20]1C3.C(O)C.Cl>C(Cl)(Cl)Cl>[ClH:17].[NH2:20][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)=[O:18]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NCC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
78 g of 1-(4-benzyloxyphenyl)-2-chloroethanone and 63 g of hexamine are dissolved in 2.2 liters of chloroform, and the mixture is stirred at room temperature overnight. The mixture is condensed to a volume of 1.1 liters, and refluxed for 3 hours. After cooling, the precipitated crystals are collected by filtration, washed and then dried. The colorless crystals thus obtained are added to a mixture of 750 ml of ethanol and 120 ml of conc. hydrochloric acid, and the mixture is refluxed for 50 minutes. After cooling, the precipitated crystals are collected by filtration, washed and then dried. 55.6 g of 2-amino-1-(4-benzyloxyphenyl)ethanone hydrochloride are obtained as colorless crystals.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)=[CH:3][CH:2]=1.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(Oc2cccc3[nH]c(C(=O)O)cc23)cc1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to Example 1 from 4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (preparation see below) and amine 5.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)[CH:14]=3)[N:9]([C:21](=[O:23])[CH3:22])[C@@H:8]([CH3:24])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Cl[CH2:26][C:27]1([CH3:31])COC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[CH:17]=[N:18][N:19]([CH2:31][C:27]5[CH:26]=[N:9][CH:8]=[CH:7][N:6]=5)[CH:20]=4)[CH:14]=3)[N:9]([C:21](=[O:23])[CH3:22])[C@@H:8]([CH3:24])[CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CC1(CCl)COC1
Reactant: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)C2CC2)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=O)N1c2ccc(-c3cnn(Cc4cnccn4)c3)cc2N(C(=O)C2CC2)C[C@@H]1C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A 40-mL sealed tube was charged with (S)-1-(4-(cyclopropanecarbonyl)-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethan-1-one (100 mg, 0.31 mmol), 3-(chloromethyl)-3-methyloxetane (100 mg, 0.83 mmol), cesium carbonate (300 mg, 0.92 mmol), and acetonitrile (10 mL). The resulting mixture was stirred overnight at 70° C. After cooling to room temperature, the reaction mixture was filtered through a short pad of celite and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B: CH3CN (12% CH3CN up to 64% in 14 min); Detector, UV220&254 nm. This afforded (S)-1-(4-(cyclopropanecarbonyl)-2-methyl-6-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (33.4 mg, 27%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.75-0.88 (m, 1H), 0.95-1.10 (m, 3H), 1.17 (d, J=6.30 Hz, 3H), 1.27 (s, 3H), 2.01-2.10 (m, 1H), 2.22 (s, 3H), 2.85-2.98 (m, 1H), 4.35-4.42 (m, 4H), 4.73-4.78 (m, 3H), 4.89-5.01 (m, 1H), 7.39-7.56 (m, 2H), 7.73 (s, 1H), 7.90 (s, 1H), 8.11 (s, 1H). MS (ESI, pos. ion) m/z 409 [M+H]+.