Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:17])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
To a mixture of 4.97 g (0.0249 mol) 1-(3-bromo-phenyl)-ethanone and molecular sieves in 50 ml methanol, 23 g (0.298 mol) ammonium acetate and 1.75 g (0.0265 mol) sodium cyanoborohydride were added and the reaction mixture was stirred 2 d (HPLC control) at 50° C. After cooling to room temperature, the molecular sieves were filtered off and washed with methanol. The solvent of the combined filtrates was evaporated and ethyl acetate and water were added to the residue. While stirring the mixture was acidified with 6N aqueous HCl solution. The aqueous phase was separated and the organic phase was extracted two times with 1N aqueous HCl solution. Ethyl acetate was added to the combined aqueous phases and the mixture was basified with 6N NaOH. The organic phase was separated and the aqueous phase was extracted two more times with ethyl acetate. The organic combined organic phases were dried over MgSO4 and the solvent evaporated at reduced pressure to afford 2.96 g (0.0148 mol) 1-(3-bromo-phenyl)-ethylamine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45](Br)[CH:46]=2)[NH:41][CH:40]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[NH2:2])[CH:5]=3)[CH:46]=2)[NH:41][CH:40]=1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C(N)=O)c1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(-c2ccc3[nH]cc(C[C@H]4CCCN4C(=O)OCc4ccccc4)c3c2)c1
Yield: 30.9 %

Procedure:
3-carbamoylphenyltri-n-butylstannane (3.076 g, 7.50 mmol) (see Preparation 9) and 3-(1-benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-bromo-1H-indole (2.81 g, 6.80 mmol) (see Preparation 35B) were reacted together in the presence of tri-o-tolylphosphine, triethylamine and palladium (II) acetate using a procedure similar to that described in Example 1. This yielded the title compound as a pale yellow foam (954 mg). Found: C,68.45; H,5.92; N,8.10; C28H27N3O3. 7/12CH2Cl2 requires: C,68.24; H,5.64; N,8.35%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26].O(C(C)(C)C)[K]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[C:18]([CH2:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1ccccc1
Temperature: -20 °C
Yield: 83 %

Procedure:
A stirred solution of 1-benzyl-4-(4-nitrophenyl)piperazine (5.95 g, 20.0 mmol) and chloromethylphenylsulfone (3.82 g, 20.0 mmol) in dry THF under nitrogen at −60° C. is treated with 1.0M KO-t-Bu in THF (44.0 mL, 44.0 mmol), warmed to −20° C. over a 1 h period, quenched with acetic acid and treated sequentially with water, saturated aqueous NaHCO3 and ether. The phases are separated and the aqueous phase is extracted with ether. The combined ethers are washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, 1:1 and 1:0 ethyl acetate:hexanes as eluent) to give the title compound as a yellow solid, 7.52 g (83% yield), mp 145-146° C., characterized by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[C:31]([N:38]1[CH2:41][CH:40]([C:42](O)=[O:43])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][C@@H:2]([NH:1][C:42]([CH:40]2[CH2:41][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39]2)=[O:43])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)c(Cl)c2)C(=O)N2CCN(c3ccccc3NS(C)(=O)=O)CC2)C1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}azetidinecarboxylate was prepared from (2R)-2-amino-3-(3,4-dichlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl) propan-1-one (Example 2, Step 2) (320 mg, 0.67 mmol), according to the procedure for Preparation XIX using Boc-azetidine-3-carboxylic acid (140 mg, 0.71 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (400 mg, 1.3 mmol), HOAT (96 mg, 0.71 mmol), and DMF (5 mL) (448 mg crude). MS (ESI, pos. ion) m/z: 654 (M+H), (ESI, neg. ion) m/z: 652 (M−H). Calc'd for C29H37Cl2N5O6S: 653.18.
Reaction SMILES: [C:1]1([S:7][C@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[NH:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:13][C@H:9]1[C@@H:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:11][C:10]1=[O:12]
Reactant: O=C1N[C@H](Sc2ccccc2)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: N[C@@H]1C(=O)N[C@@H]1Sc1ccccc1

Procedure:
To a solution of 1.5 g of (3R,4R)-4-phenylthio-3-tritylamino-2-oxoazetidine in 20 ml of acetone is added 0.72 g of p-toluenesulfonic acid monohydrate under ice-cooling. Following the procedure to Reference Example 45B, there is obtained 1.25 g of tosyl salt of (3R,4R)-3-amino-4-phenylthio-2-oxoazetidine.
Reaction SMILES: C([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C@@H:26]([CH2:30][CH2:31][CH2:32][NH:33][CH:34]2[C:43]3[N:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH2:37][CH2:36][CH2:35]2)[C:27]([OH:29])=[O:28])=[O:24])=[CH:19][N:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(OC(C)(C)C)=O.[ClH:44].O1CCOCC1>CO>[ClH:44].[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C@@H:26]([CH2:30][CH2:31][CH2:32][NH:33][CH:34]2[C:43]3[N:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH2:37][CH2:36][CH2:35]2)[C:27]([OH:29])=[O:28])=[O:24])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC2CCCc3cccnc32)C(=O)O)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(N[C@@H](CCCNC1CCCc2cccnc21)C(=O)O)c1ccc(CNCc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The compound obtained in Example 12-5 (26.8 mg) was dissolved in methanol (0.5 ml), and 4 mol/l hydrochloric acid/dioxane solution (0.5 ml) was added. The mixture was stirred for 4.5 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (1 g, chloroform/methanol/water=7/3/0.5). The obtained product was added with an aqueous solution of hydrochloric acid and concebtrated, and then azeotropically distilled with water. The resulting solid was washed with ether to obtain a hydrochloride of the title compound (25.8 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)C>[CH2:13]([O:12][C:11]1[C:2]2[N:3]([CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:1]=2)[C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([Cl:15])=[C:6]([Cl:16])[CH:5]=2)[CH3:14]
Reactant: CCOc1nc2cc(Cl)c(Cl)cc2nc1N
Reactant: CCOC(=O)C(=O)CBr
Agent: CC(C)C
Product: CCOC(=O)c1cn2c(n1)c(OCC)nc1cc(Cl)c(Cl)cc12
Yield: 10.9 %

Procedure:
A solution of 1 g of the product of Step A, 1 g of ethyl bromopyruvate and 50 ml of dimethylethane was stirred at room temperature for 5 days and the mixture was filtered to recover 0.51 g of a white crystalline solid. The latter was chromatographed over silica gel and was eluted with chloroform to obtain 0.15 g of ethyl 4-ethoxy-7,8-dichloroimidazo-[1,2-a]-quinoxaline-2-carboxylate in the form of a white crystalline solid melting at 256°-258° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:16][CH3:17])[C:13](O)=[O:14])=[CH:8][CH:9]=2)[C:4]([CH3:19])([CH3:18])[CH2:3]1.S(Cl)([Cl:23])=O>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:16][CH3:17])[C:13]([Cl:23])=[O:14])=[CH:8][CH:9]=2)[C:4]([CH3:19])([CH3:18])[CH2:3]1
Reactant: CCC(Oc1ccc2c(c1)C(C)(C)CC2(C)C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCC(Oc1ccc2c(c1)C(C)(C)CC2(C)C)C(=O)Cl

Procedure:
A mixture of 100.5 g (0.364 mole) of 2-(1,1,3,3-tetramethyl-5-indanoxy)-butyric acid and 67 ml of thionyl chloride were refluxed for 2 hours. The excess thionyl chloride was evaporated.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCN(CCCO)CC1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NC1CCN(CCCOC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 92.5 %

Procedure:
Treatment of 4-benzamido-1-(3-hydroxypropyl) piperidine with benzoyl chloride as in the previous example gave 3.4 grams (92.5% yield) of the title compound, m.p. 146°-7° C. Crystallisation from ethanolic hydrogen chloride afforded the hydrochloride, m.p. 211°-212° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)(=O)C.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][C:32]2=[O:41])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:34][CH2:33][C:32]4=[O:41])[CH2:27][CH2:26]3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN3CCC(N4C(=O)CCc5ccccc54)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde(0.203 g) and acetic acid(0.063 ml) were added to a 1,2-dichloroethane solution (5 ml) of 1-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.170 g), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride(0.235 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=100:0→90:10). The purified product was condensed to dryness to give the title compound(0.205 g) as pale yellow amorphous.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[CH:28][C:29]([F:42])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:33]=5[CH3:41])[CH:31]=4)=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:51][C:52]1([F:56])[CH2:55][NH:54][CH2:53]1.CCN(CC)CC>C1COCC1>[F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[CH:28][C:29]([F:42])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:33]=5[CH3:41])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:54]4[CH2:55][C:52]([F:56])([F:51])[CH2:53]4)[N:21]=3)[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1cc(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)ccc1F
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)O)ccc1-c1cc(-c2cnc(N3CC(F)(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)ccc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of the title compound from Step D (22 mg, 0.031 mmol), 3,3-difluoro-azetidine hydrochloride (20 mg, 0.155 mmol) and Et3N (31.3 mg, 0.309 mmol) in THF (5 mL) was stirred at 60° C. overnight. The solvent was removed. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.1% TFA, to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 8.34 (s, 1H), 8.08 (s, 1H), 8.02 (d, J=8 Hz, 1H), 7.93 (s, 1H), 7.77 (s, 2H), 7.17-7.42 (m, 4H), 5.72 (d, J=8.0 Hz, 1H), 4.90 (d, J=17 Hz, 1H), 4.55 (m, 4H), 4.40 (m, 1H), 4.08 (d, J=17 Hz, 1H), 2.35 (s, 3H), 0.77 (d, J=7 Hz, 3H). LCMS=725.3 (M+H)+
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:11]1[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:29](=[O:40])[NH:30][C@@H:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH3:32])[CH:17]=2)[C:12]1=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O.CO.C1COCC1>[CH2:4]([N:11]1[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:29](=[O:40])[NH:30][C@@H:31]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH3:32])[CH:17]=2)[C:12]1=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)CCCCc1cc2cc(C(=O)N[C@H](C)c3ccc(F)cc3)ccc2c(=O)n1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(CCCCC(=O)O)cc2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide monohydrate (4.0 equiv.) in water (0.66 M) was added to a stirred mixture of (R)-methyl 5-(2-benzyl-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (1 eq) in MeOH/THF (v/v=1/4) and the mixture was stirred at room temperature. After 2 h, the mixture was neutralized with 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered and evaporated to dryness. To the residue was added Et2O and sonicated, upon which some solid precipitated. The solids were filtered, triturated with Et2O and dried to yield (R)-5-(2-benzyl-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid. LCMS [M+H]+=501. 1H NMR (CDCl3, 500 MHz) δ ppm: 8.44 (d, 1H, J=8.5 Hz), 7.92 (br s, 1H), 7.71 (d, 1H, J=8.0 Hz), 7.40 (dd, 2H, J=5.0 Hz, J=8.5 Hz), 7.32-7.23 (m, 3H), 7.12 (d, 2H, J=7.5 Hz), 7.06 (t, 2H, J=9.0 Hz), 6.42 (s, 1H), 5.43 (br s, 2H), 5.39-5.35 (m, 1H), 2.63 (t, 2H, J=7.5 Hz), 2.37 (t, 2H, J=6.5 Hz), 1.70-1.64 (m, 4H), 1.63 (d, 3H, J=7.0 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:20][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:23]=2)=[O:18])=[C:10]([CH3:31])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:31])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:20][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nnc(Cc2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1nnc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5-{[(5-Benzyl-[1,3,4]oxadiazole-2-carbonyl)-amino]-methyl}-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (412 mg, 0.94 mmol), 4 mL TFA and 8 mL DCM was stirred of room temperature for 2 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). The product containing fractions were lyophilised, then dissolved in 1 mL MeOH and the resulting mixture was filtered over a MeOH flushed PL-HCO3 MP-resin column. The column was washed with MeOH, the solvent was removed and the crude product was dissolved in water/ACN and lyophilised to yield the title compound. 1H-NMR (DMSO-d6, 400 MHz) 9.33 (t, 1H), 7.29-7.39 (m, 5H), 6.11 (s, 1H), 5.71 (bs, 2H), 4.34-4.36 (m, 4H), 2.30 (s, 3 H), 2.17 (s, 3H); LCMS (method A) RtA=0.814 min; [M+H]+=338.0.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].NO.[OH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]2[C:21]=1[C:20](=O)[CH2:19][CH2:18]2>CO.C(OCC)(=O)C>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]2[C:21]=1[C:20](=[N:2][OH:3])[CH2:19][CH2:18]2
Reactant: Cc1ccc(O)c2c1CCC2=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c2c1CCC2=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28 Grams of hydroxylamine hydrochloride and 56 g of potassium carbonate were added in 400 ml of methanol, and the mixture was refluxed by hetting for 30 minutes. After cooling the reaction mixture to a room temperature, the supernatant liquor was collected by separation to prepare a methanol solution of hydroxylamine. To this methanol solution of hydroxylamine was added 16.2 g of 7-hydroxy-4-methyl-1-indanone and refluxed by heating for 5 hours under stirring condition. The reaction mixture was concentrated to dryness under a reduced pressure. To the residue thus obtained was added 200 ml of ethyl acetate, then the insoluble matter was removed by filtration. The filtrate was concentrated to dryness under a reduced pressure, and the residue was recrystallized from methanol to obtain 17.6 g of 7-hydroxy-4-methyl-1-indanone oxime in the form of colorless needle-like crystals.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:25][CH2:24][CH2:23][C:12]=4[N:13]=[C:14]([N:16]4[CH2:19][CH2:18][C@H:17]4[C:20]([OH:22])=O)[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F:26][C:27]1[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:25][CH2:24][CH2:23][C:12]=4[N:13]=[C:14]([N:16]4[CH2:19][CH2:18][C@H:17]4[C:20]([NH:33][C:30]4[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:22])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)nc1
Reactant: O=C(O)[C@@H]1CCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)nc1)[C@@H]1CCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
To a solution of (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)azetidine-2-carboxylic acid (300 mg, 0.909 mmol) in DMF (3 mL) was added 6-fluoropyridin-3-amine (203 mg, 1.818 mmol), HATU (414 mg, 1.091 mmol) and DIPEA (0.26 mL, 1.45 mmol). The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with water (8×30 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 40 mg of (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide as the formate salt. 1H NMR (400 MHz, CD3OD, TFA salt) δ (ppm): 0.40-0.60 (m, 2H), 0.70-0.85 (m, 2H), 1.58-1.70 (m, 1H), 2.20-2.37 (m, 2H), 2.58-2.69 (m, 1H), 2.79-2.97 (m, 3H), 2.98-3.06 (m, 2H), 4.21-4.38 (2H), 5.16 (dd, 1H), 6.16 (s, 1H), 7.05 (dd, 1H), 8.05-8.17 (m, 1H), 8.30 (s, 1H). The other enantiomer was prepared using the (R) chiral starting material.
Reaction SMILES: COC(OC)(C)C.[C@H]1(OC2C=CC=CC=2[C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:30]([OH:32])(=[O:31])[C:29]1[CH:33]=[CH:34][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc(-c2ccccc2O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 400.8 %

Procedure:
Acetone (5.6 ml) and dimethoxypropane (5.6 ml) were added to 4-(2-(α-D-mannopyranosyloxy) phenyl)benzoic acid (0.54 g, 1.43 mmol) to form a heterogeneous mixture. A catalytic amount of p-toluenesulfonic acid monohydrate was introduced and the reaction was stirred at room temperature for 45 minutes, at which point a clear, homogeneous solution was obtained. The solvent was removed in vacuo and the yellow oily residue taken up in ethyl acetate, washed with saturated sodium bicarbonate then saturated sodium chloride, dried (MgSO4) and concentrated in vacuo to afford 4-(2-(2,3:4,6-di-O-isopropylidene)α-D-mannopyranosyloxy)phenyl)benzoic acid (0.70 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([O:23][CH2:24][O:25][CH3:26])=[C:18]([N+:20]([O-])=O)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:23][CH2:24][O:25][CH3:26])=[C:18]([CH:19]=2)[NH2:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C=CCS(=O)(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1N
Yield: 78.9 %

Procedure:
Under one atmosphere, a solution of 300 mg of 5-[3-(4-chlorophenylsulfonyl)-1-propenyl]-2-methoxymethoxy nitrobenzene in 8 ml of ethyl acetate and 500 mg of 10% palladium carbon added thereto were stirred in the presence of hydrogen gas. The resultant reaction mixture was filtered and then concentrated under a vacuum, to produce 220 mg of 5-[3-(4-chlorobenzenesulfonyl)propyl]-2-methoxymethoxy aniline in the form of a colorless oily substance. The yield was 73%. This product was put to use in its unpurified form in the following reaction.