Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.CC([O-])=O.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CCCCCCC>[C:1]([O:10][C:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: c1ccc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCCCC
Product: CCCCCCCC(=O)Oc1cccc2ccccc12
Reaction time: 5 h
Yield: 73 %

Procedure:
The reaction was carried out in a glass reactor furnished with a thermometer, mechanical stirrer, Dean Stark type collector equipped with a reflux condenser and gas and liquid tubes. The reactor was charged with 40 g. of octanoic acid, 10 g. (78 m mols) of naphthalene, 8 g. of heptane, 0.34 g. (1.5 millimols) of Pd(OAc)2 0.45 g (1.5 m mols of Sb(OAc)3 and 0.15 g (1.5 m mols) of KOAc. Dean Stark Collector was filled with heptane. The reaction was carried out at 170° C. with vigorous stirring for 5 hours. GLC analysis showed that 57 m mols (73% yield) of naphthyl octanoate were produced.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:35])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1cccc(C2CC3(NC(=O)NC3=O)c3cc(Br)ccc3O2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: COc1cccc(C2CC3(NC(=S)NC3=O)c3cc(Br)ccc3O2)c1
Yield: 38.5 %

Procedure:
A suspension of 6-bromo-2-(3-methoxyphenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (250 mg, 0.64 mmol) and Lawesson's Reagent (250 mg, 0.62 mmol) in dry 1,4-dioxane (20 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-methoxyphenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (100 mg, 45%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1)[C:7](=[O:28])[CH:6]=[CH:5]2.[CH3:29][O-:30].[Na+]>CO.O.C(OCC)(=O)C>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([O:30][CH3:29])=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]2=[O:28])[CH2:19][CH2:18]1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3cc(Cl)ncc32)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc2ccc(=O)n(CCN3CCC(N)CC3)c2cn1
Temperature: 150 °C
Yield: 64 %

Procedure:
A solution of tert-butyl {1-[2-(6-chloro-2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 129, 335 mg, 0.83 mmol) was treated with a solution of sodium methoxide in methanol (0.5 M, 4 mL). The reaction was sealed in a tube and heated at 150° C. for 4 hours using microwave irradiation. The reaction was diluted with water and ethyl acetate. The layers were separated. The aqueous phase was washed with ethyl acetate twice. The organic extracts were combined dried over magnesium sulfate and evaporated at reduced pressure to give 116 mg (64%) of the crude product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C@@H:3]([N:5]([CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[CH3:26][C:27]([S@:30]([NH2:32])=[O:31])([CH3:29])[CH3:28]>C1COCC1.[Cl-].[Na+].O>[C:27]([S@:30](/[N:32]=[C:15](/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)\[CH2:14][CH2:13][N:5]([C@H:3]([C:2]([CH3:25])([CH3:24])[CH3:1])[CH3:4])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:31])([CH3:29])([CH3:28])[CH3:26]
Reactant: C[C@H](N(CCC(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C)C(C)(C)C
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](N(CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(F)cc1)C(=O)OC(C)(C)C)C(C)(C)C
Yield: 41.2 %

Procedure:
To a solution of (S)-tert-butyl 3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (1.50 g, 4.27 mmol) in dry THF (20 mL) was added Ti(Oi-Prl)4 (2.46 g, 8.55 mmol) and (R)-2-methylpropane-2-sulfinamide (1.03 g, 8.55 mmol) under N2, and the mixture was refluxed overnight. After the reaction was over, the solution was poured into 20 mL brine and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by chromatography to afford tert-butyl (E)-3-((R)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl((S)-3,3-dimethylbutan-2-yl)carbamate (800 mg, 42%). 1H NMR (CDCl3): 0.75 (s, 9H), 1.26 (m, 12H), 1.47 (s, 8H), 3.27 (m, 2H), 3.49 (m, 2H), 3.91 (m, 1H), 7.14 (m, 2H), 7.89 (m, 1H), 8.25 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C([Mg]Cl)(C)C.[F:13][C:14]1([F:30])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26](OC)=[O:27])[CH2:15]1>C1COCC1>[F:30][C:14]1([F:13])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26](=[O:27])[NH:7][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:15]1
Reactant: Nc1cnccn1
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)Nc1cnccn1
Reaction time: 0.25 h

Procedure:
To a stirred solution of pyrazin-2-amine (4.30 g, 45.2 mmol) in 50 mL of THF was added isopropylmagnesium chloride (16.96 mL, 33.9 mmol) dropwise under nitrogen atmosphere. A solid precipitated from the solution. After 15 min, a solution of (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate 116A (3 g, 11.31 mmol) in 50 mL of THF was added and stirred for 2 hr. The solvent was evaporated to dryness at the reduced pressure. The residue was suspended in ethyl acetate, washed with water, brined and dried. Evaporation of the solvent furnished a solid, which was chromatographed (20% ethyl acetate, CH2Cl2) to give 116B. LC/MS [M+H]+: 329; Ret time (Method F): 2.42 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 1.5 h
Yield: 83.8 %

Procedure:
To a 250 mL round-bottom flask equipped with a large stir bar was added (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (10.9 g, 25.5 mmol), then THF (75 mL) and methanol (75 mL). To the stirred solution was added aq. lithium hydroxide (2.0 M, 38 mL, 77 mmol). The mixture was vigorously stirred for 1.5 h. The volatiles were removed organics were removed in vacuo and the resulting aqueous solution and solid residue was transfered to a 500 mL separatory funnel. The aqueous phase was adjusted to pH 2.5 using aqueous 2N HCl and was then extracted with EtOAc (3×100 mL). The combined organics were washed with aqueous sat. NaCl adjusted to pH 2.5 with aqueous HCl, dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid as a colorless foam (8.82 g, 84%). MS: MS m/z 413.2 (M++1).
Reaction SMILES: N[C:2](N)=[S:3].[N+]([O-])([O-])=O.[NH4+].O1[CH2:27][CH:11]1[CH2:12][S:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][S:22][CH2:23][CH:24]2OC2)[CH2:17][CH2:16]1.[S:28](=O)(=O)(O)O>C1(C)C=CC=CC=1.CO>[S:3]1[CH2:2][CH:24]1[CH2:23][S:22][CH2:21][CH:18]1[CH2:19][CH2:20][CH:15]([CH2:14][S:13][CH2:12][CH:11]2[S:28][CH2:27]2)[CH2:16][CH2:17]1
Reactant: NC(N)=S
Reactant: O=S(=O)(O)O
Reactant: C1CC(CSCC2CO2)CCC1CSCC1CO1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C1CC(CSCC2CS2)CCC1CSCC1CS1
Yield: 80 %

Procedure:
305 g of thiourea, 3000 ml of methanol, 1500 ml of toluene, 10 g of ammonium nitrate, and 332 g of 1,4-bis(β-epoxypropylthiomethyl)cyclohexane were mixed and reacted at 20° C. for 9 hours in a nitrogen atmosphere. During the reaction, no polymer was deposited. After the reaction, 3800 ml of toluene and 460 ml of 10% aqueous solution of sulfuric acid were put to the reaction vessel to extract the reaction product. Then, the extracted product was washed with 300 ml of water four times, and toluene was removed by distillation. As a result, 295 g of 1,4-bis(β-epithiopropylthiomethyl)cyclohexane (in formula (5), p=1, q=1) was obtained. The yield was 80%. The results are shown in Table 3.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][CH:69]([CH3:71])[CH3:70])=[CH:64][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:61][C:62]3[CH:63]=[CH:64][C:65]([O:68][CH:69]([CH3:71])[CH3:70])=[CH:66][CH:67]=3)[C:57]([O:59][CH3:60])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Reaction time: 0.17 h
Yield: 39.5 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.052 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) in N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (12 uL, 0.070 mmol). The reaction was stirred for 10 min, and the methyl (2S)-2-amino-3-(4-isopropoxyphenyl)propanoate (16 mg, 0.070 mmol) was added. The reaction mixture was stirred for 2 h. at r.t. and was purified by RP-HPLC (pH=2) to afford the desired product (6 mg, 30%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=507.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH:8]([CH:10]([C:12]([OH:14])=[O:13])[OH:11])[OH:9].C(N(CC)CC)C.[C:23](#[N:26])[CH:24]=[CH2:25]>O>[C:23]([CH2:24][CH2:25][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH:8]([CH:10]([C:12]([OH:14])=[O:13])[OH:11])[OH:9])#[N:26]
Reactant: C=CC#N
Reactant: NCCCCNC(=O)C(O)C(O)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: N#CCCNCCCCNC(=O)C(O)C(O)C(=O)O

Procedure:
2.01 Grams (9.127 mmoles) of N-(4-aminobutyl)tartaric acid monoamide (IX) obtained in 1. was dissolved in 40 ml of water, and after adding 1.273 ml of triethylamine and then 0.726 ml of acrylonitrile, the resulting mixture was stirred for 27 hours at room temperature. The reaction solution was then dried to solid under reduced pressure. After adding 20 ml of water to the residual solid, the resulting solution was passed through a column packed with 300 ml of Dowex® 1×4(OH-), and after washing with 1.2 liters of water, eluted with 0.5N aqueous acetic acid solution. The fractions containing the objective compound were collected and concentrated under reduced pressure to obtain 2.235 g of a syrup-form N-[4-(2-cyanoethyl)aminobutyl]tartaric acid monoamide (XI) (yield, 89.6%).
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1.CCN(CC)CC.[F:38]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C1COCC1>>[F:38][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CN(C[C@H](C[C@H]1CC[C@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 39.2 %

Procedure:
A mixture of tert-butyl (S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (3 g, 7 mmol), Et3N (12 mL, 88 mmol), NEt3(HF)3 (4.71 mL, 29 mmol) and perfluorobutanesulfonyl fluoride (5.21 mL, 29 mmol) was stirred in THF (70 mL, 1 mmol/10 mL) at 50° C. until HPLC revealed complete conversion. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL), dried over MgSO4 and evaporated. The residue was then purified by prep HPLC to give tert-butyl (S)-1-(trans-4-fluorocyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (1.16 g, 40%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.41(d, 9 H), 1.68(m, 6 H), 1.96(m, 3 H), 2.98(d, 3 H), 3.20(m, 1 H), 3.52(m, 1 H), 3.90(m, 1 H), 5.13(d, 2 H), 7.33(m, 5 H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Na].[CH3:24]I.O>O1CCOCC1>[CH3:24][O:15][CH2:14][CH:13]([O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:21])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: CC(CO)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CI
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: COCC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 67 %

Procedure:
6 g of β-[4-(4-trifluoromethylphenoxy)phenoxy]propanol was dissolved in 30 ml of dioxane and 0.46 g of sodium was added to the solution. The mixture was then heated for 3 hours while refluxing. 3.1 g of methyl iodide was added thereto and the resulting mixture was heated for 6 hours while refluxing. The reaction mixture was then poured into an appropriate amount of water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The ether was removed by distillation and the residue was distilled under reduced pressure to obtain 4.2 g of the desired product having a boiling point of 160° to 165° C./2 mmHg.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[S:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH:16](Br)[CH3:17].Cl.[OH-].[Na+]>C(O)C.CN(C=O)C>[S:12]1[CH2:17][CH2:16][N:9]2[C:8]3[CH:13]=[CH:14][C:5]([CH2:3][OH:4])=[CH:6][C:7]=3[N:11]=[C:10]12
Reactant: COC(=O)c1ccc2[nH]c(=S)[nH]c2c1
Reactant: CC(Br)Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: OCc1ccc2c(c1)nc1n2CCS1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.9 %

Procedure:
To a round bottomed flask was added 2.83 grams of 2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester, 2.55 grams of dibromoethane and 50 ml DMF and 50 ml ethanol. The mixture was refluxed for 10 hours. Then it was concentrated to dry on a rotary evaporator. The solid was next dissolved in 100 ml THF and 20 ml of 1 M LiAlH4 (in THF) was next injected within five minutes. The reaction media was stirred at room temperature for one hour. Ethanol was next added (˜10 ml), followed by 50 ml 2N HCl. The aqueous layer was adjusted to basic Ph=14 with 10N sodium hydroxide. The aqueous was extracted with 2×500 ml ethyl acetate. The combined organic layers was dried over magnesium sulfate. Filter off the drying agent and cocentrate yielded 2.04 grams (60%) product. MS: 207.0 (M+H). H-NMR(DMSO): □ 7.34(m, 2H), 7.08 (m, 1H), 5.15(m, 1H, OH), 4.53 (m, 2H, CH2), 4.34 (m, 2H, CH2), 4.00 (m, 2H, CH2).
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)C=[CH:13]1>ClCCl>[CH:6]([C:7]1[C:15]2[C:20](=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[NH:12][CH:13]=1)=[O:10]
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMF (0.389 mL) was added dropwise to a solution of oxalyl chloride (0.440 mL) in dry dichloromethane (5 mL) at 0° C. The resulting solution was stirred at 0° C. for 10 min. A solution of 1H-indole-6-carbonitrile (D12) (0.650 g) in dry dichloromethane (5 mL) was added to the reaction mixture. The reaction mixture was warmed to RT and stirred at that temperature for 45 min. The solvent was evaporated. THF (50 mL) was added, followed by addition of aqueous NaOH (2 M, 50 mL) and water (200 mL). The biphasic mixture was allowed to stand for 10 min. EtOAc (300 mL) and water (100 mL) was added. The organic fraction was separated and was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 3-formyl-1H-indole-6-carbonitrile (D13) as a orange solid (604 mg). δH (DMSO-d6, 400 MHz): 7.59 (1H, dd), 8.05 (1H, d), 8.24 (1H, m), 8.56 (1H, s), 10.00 (1H, s), 12.62 (1H, br s). MS (ES): C10H6N2O requires 170; found 169.0 (M−H+).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[N:24]=[CH:25][C:18]=12>CC(N(C)C)=O>[CH2:2]([N:9]1[CH2:12][CH:11]([O:13][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([C:26]4[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=4)[N:24]=[CH:25][C:18]=23)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Reactant: OC1CN(Cc2ccccc2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CN(Cc5ccccc5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
1-Benzyl-azetidin-3-ol hydrochloride salt (0.59 mmol, 117 mg) and sodium hydride were dissolved in dimethyl acetamide (2 mL) and stirred at room temperature for 30 minutes. 4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.49 mmol, 150 mg) was added slowly and the mixture was stirred at 70° C. for 20 minutes. The reaction mixture was quenched with water followed by an extraction with ethyl acetate. Removal of organic solvents in vacuo and purification by flash chromatography provided compound A23 as a white solid (88 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90 (s, 1H); 8.53 (s, 1H); 8.30 (d, 2H); 8.16 (d, 2H); 7.43 (m, 5H); 6.19 (m, 1H); 4.59 (m, 2H); 4.42 (d, 1H); 4.00 (d, 1H); 3.65 (d, 1H); 3.35 (m, 1H); 3.30 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]([CH3:23])=O.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH:21]([NH:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=3)[CH2:13]2)[CH2:16][CH2:15]1)([CH3:23])[CH3:20]
Reactant: CC(C)=O
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3aR,4S,6aS)-2-(6-(Trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (44 mg, 0.162 mmol) and acetone (14.13 mg, 0.243 mmol) were combined in dichloromethane (0.5 mL). Acetic acid (0.5 mL) was added. The reaction mixture was stirred at ambient temperature for 30 minutes, then PS-cyanoborohydride (146 mg, 0.324 mmol) was added. After 18 hours, the reaction mixture was filtered and the solvent removed under a stream of nitrogen. The crude material was applied to a 4 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane to give to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.57-7.52 (m, 1H), 6.99 (d, J=7.2, 1H), 6.55 (d, J=8.6, 1H), 3.62-3.54 (m, 1H), 3.54-3.45 (m, 2H), 3.25 (dd, J=10.7, 4.3, 1H), 3.03 (dd, J=11.8, 5.9, 1H), 2.83 (dt, J=12.4, 6.2, 1H), 2.76-2.67 (m, 1H), 2.49-2.41 (m, 1H), 2.02-1.92 (m, 2H), 1.45-1.29 (m, 3H), 1.06 (d, J=6.2, 3H), 1.03 (d, J=6.2, 3H); MS (ESI+) m/z 314 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:10][CH:5]2[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]2)=[CH:16][C:15]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Product: CN1C(C)(C)CC(Oc2ccc(Cl)c(C(F)(F)F)c2)CC1(C)C
Product: Cl

Procedure:
Was prepared according to method A from 1,2,2,6,6-pentamethyl-piperidin-4-ol and 4-chloro-3-trifluoromethylphenol. Mp 240-245° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(ON)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (10 mL) were added 4-(aminooxy)-1-methylpiperidine 50 (0.129 g, 0.99 mmol), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 16 h, diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography to give 51 (0.065 g, 31%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][NH2:7])[CH3:3].[CH2:8]([N:17]=[C:18]=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>C(Cl)Cl>[N:2]([CH2:4][CH2:5][CH2:6][NH:7][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:17][C:18]([NH:7][CH2:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[O:19])=[O:16])([CH3:3])[CH3:1]
Reactant: O=C=NCCCCCCN=C=O
Reactant: CN(C)CCCN
Solvent: ClCCl
Product: CN(C)CCCNC(=O)NCCCCCCNC(=O)NCCCN(C)C
Yield: 59.3 %

Procedure:
204.3 g of dimethylaminopropylamine are added dropwise to a solution of 168.2 g of hexamethylene diisocyanate in 100 ml of methylene chloride and the mixture is refluxed overnight, in the process of which crystals precipitate. The crystals are filtered with suction at room temperature, washed with CH2Cl2 and dried. Recrystallisation from a mixture of 1000 ml of acetone and 800 ml of ethanol yields 221.0 g (59.3%) of product with a melting point of 159° C. Tritration: 2 equivalents=376.7 g (theory 372.6 g).