Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].[CH2:7]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:7][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][CH2:10]3)[CH2:16][CH2:15]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCC3(CCN(C(=O)OC(C)(C)C)C3)CC2)cc1
Yield: 35 %

Procedure:
Sodium t-butoxide (599 mg, 6.24 mmol, 3.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (500 mg, 2.08 mmol, 1.0 eq.) and 1-chloro-4-methoxybenzene (389 mg, 2.08 mmol, 1.0 eq.) in toluene (25 ml) and the reaction mixture was degassed with Nitrogen. BINAP (51.8 mg, 0.083 mmol, 0.04 eq.) and Pd(OAc)2 (10 mg, 0.0416 mmol, 0.02 equiv) were added and the resulting mixture was heated at reflux for 16 h. The reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to afford the crude product which was purified by column chromatography (silica gel; 0-10% EtOAdhexanes) to give the pure product as an oil. Yield: 35% (250 mg, 0.722 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1.[C:28](Br)([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1
Reactant: CC(C)(C)Br
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)OC(C)(C)C)CC3)nc12
Temperature: 55 °C
Reaction time: 72 h

Procedure:
A suspension of 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (30 mg, 83 μmol) and benzyltriethyl-ammonium chloride (19 mg, 83 μmol) in DMF (1.0 mL) was gently heated until it became a solution. Tert-butyl bromide (2974, 2.64 mmol) and K2CO3 (171 mg, 1.24 mmol) were added and the mixture was stirred at 55° C. for three days. Additional tert-butyl bromide (139 μL, 1.24 mmol) and K2CO3 (171 mg, 1.24 mmol) were added and the mixture was stirred at 55° C. for one more day. PrepHPLC purification afforded the title compound. HPLC-Retention time (XE Metode 7 CM): 2.29 minutes. Detected “M+1”-mass: 422.18. Calculated “M+1”-mass: 422.17. 1H NMR (DMSO, 300 MHz): δ=8.27-8.22 (m, 1H), 8.16 (dd, 1H, J=8.0, 1.5 Hz), 8.00 (d, 1H, J=8.2 Hz), 7.40 (d, 1H, J=8.2 Hz), 7.22 (d, 1H, J=8.3 Hz), 5.51 (s, 2H), 4.04 (s, 3H), 1.54-1.40 (m, 4H), 1.38 (s, 9H) ppm.
Reaction SMILES: C(O)=O.[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7](=[O:15])[CH:6]=1.[CH:16]([C:18]1[CH:35]=[CH:34][C:21]([C:22]([O:24][CH:25]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.C(N(CC)CC)C>C(OCC)(=O)C>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7](=[O:15])[C:6]=1[CH2:16][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:25]([C:27]([F:32])([F:33])[C:28]([F:30])([F:31])[F:29])[CH3:26])=[O:23])=[CH:34][CH:35]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CC(OC(=O)c1ccc(C=O)cc1)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CC(OC(=O)c1ccc(Cc2c(O)c3ccccc3oc2=O)cc1)C(F)(F)C(F)(F)F
Temperature: 140 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Formic acid (35.8 ml) was added to 4-Hydroxycoumarin (15.8 g, 97.5 mmol) and aldehyde 3 (28.9 g, 97.6 mmol). Triethylamine (43 ml) was added (exothermic) at 0° C. It was warmed to 140° C. and stirred for 4 h at this temperature. The yellow solution was cooled to rt, ethyl acetate was added, it was washed with 1 N HCl and brine, it was dried over Na2SO4 and the solvent was removed. The slightly yellow solid was recrystallized from ethylacetate to yield the title compound as a white solid in 98% purity (60% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]1([S:23](Cl)(=[O:25])=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc3ccccc23)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 1-naphthylsulfonyl chloride according to METHOD A, giving a crude product that was purified by flash column chromatography on silica gel eluting with 2% methanol in DCM. This gave the pure title compound (3.93 g, 89%). MS (Ionspray, [M+H]+) m/z 376; Anal. Calcd. (found) for C17H16N2O4S2: C, 54.2 (54.02)%; H, 4.3 (3.9)%; N, 7.4 (7.1)%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:26])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH:16]2[C:22]([O:24][CH3:25])=[O:23])=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)C>[NH2:33][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:26])[CH:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17]1
Reactant: [BH3-]C#N
Reactant: COC(=O)C1CC(=O)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COC(=O)C1CC(N)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 91.3 %

Procedure:
To 5 mL of an ethanol suspension containing 0.15 g of methyl 1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)-4-oxopiperidine-2-carboxylate, 0.16 g of ammonium acetate and 0.20 g of molecular sieves 3A were added at room temperature. After the mixture was stirred for 2 hours and 55 min at room temperature, 21 mg of sodium cyanoborohydride was added, and stirred for 1 hour and 40 min. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.11 g of methyl 4-amino-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate as a brown foam. (2) According to a procedure similar to Example 179, methyl 4-((3-fluoro-4-methylbenzyl)amino-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate was obtained from methyl 4-amino-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate.
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].C(N(CC)C(C)C)(C)C.CS(C)=O.O>ClCCl>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[O:29])[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCCCCCCO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCCCCCC=O)C1
Reaction time: 0.67 h
Yield: 107.1 %

Procedure:
To a stirred solution of (S)-3-(1-carbamoyl-1,1-diphenylmethyl)-1-(7-hydroxyhept-1-yl)pyrrolidine (31.00 g, 78.57 mmol); N,N-diisopropylethylamine (68.4 mL, 392.8 mmol); and methyl sulfoxide (60.7 mL, 785.7 mmol) in dichloromethane (780 mL) under an atmosphere of nitrogen at −15° C., was added sulfur trioxide pyridine complex (37.5 g, 235.71 mmol) portion-wise over a 40 min. period. The reaction mixture was maintained between −10° C. and −20° C. during the addition. The reaction was then stirred in this temperature range for 40±10 min. Deionized water (300 mL) was added and the mixture was stirred for 10 minutes. The organic layer was separated and washed with deionized water (200 mL), followed by saturated aqueous sodium chloride (200 mL) and the organic layer was then dried with magnesium sulfate (10 g). The magnesium sulfate was filtered off and washed with dichloromethane (50 mL) and the solvent was reduced in vacuo. The resultant syrup was washed with petroleum ether (2×200 mL) to remove the remaining pyridine and DMSO and the resulting white solid was dried in vacuo to give 33.02 g of the title intermediate (98% yield; >93% purity by chiral HPLC Method A).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:7]=1.[H][H]>CO.[Pd]>[N:17]1([C:4]2[C:5]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:14])[CH3:15])=[N:6][CH:7]=[CH:2][N:3]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: [H][H]
Reactant: CC(C)NCC(O)COc1ncc(Br)nc1N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)NCC(O)COc1nccnc1N1CCOCC1
Reaction time: 0.17 h

Procedure:
7.5 g of 5-bromo-3-morpholinyl-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine are dissolved in 80 ml of methanol and hydrogenated in the presence of 0.4 g of palladium on charcoal (5% strength) at 20°-30° C. under normal pressure. After 10 minutes, the reaction is complete and the calculated amount of hydrogen has been taken up. The catalyst is then filtered off and the filtrate is evaporated in a waterpump vacuum. The residue is partitioned between water and ether. The aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. 3-Morpholinyl-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, melting point 74°-76° C., is thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[CH3:14][C:15]1[CH:16]=[C:17]([P:24]([C:26]2[CH:31]=[C:30]([CH3:32])[C:29]([O:33][CH3:34])=[C:28]([CH3:35])[CH:27]=2)Cl)[CH:18]=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22]>C1COCC1.CC(OC)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:24]([C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([O:33][CH3:34])=[C:28]([CH3:35])[CH:27]=1)[C:17]1[CH:16]=[C:15]([CH3:14])[C:20]([O:21][CH3:22])=[C:19]([CH3:23])[CH:18]=1
Reactant: COc1c(C)cc(P(Cl)c2cc(C)c(OC)c(C)c2)cc1C
Reactant: Brc1ccccc1I
Agent: CC(C)[Mg]Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1c(C)cc(P(c2cc(C)c(OC)c(C)c2)c2ccccc2Br)cc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 9.67 g (34.2 mmol) of 1-bromo-2-iodobenzene in 30 ml of THF are added dropwise, at −78° C., 17.6 ml (37.6 mmol) of an isopropylmagnesium chloride solution (2 molar in THF). The mixture is stirred at a temperature between −30° C. and −40° C. for a further 1 hour, then cooled again to −78° C., and a solution of 12.66 g (37.6 mmol) of bis(3,5-dimethyl-4-methoxyphenyl)chlorophosphine in 10 ml of THF and 10 ml of TBME is added. The cooling is removed and the reaction mixture is stirred at room temperature overnight. The resulting solution is admixed with 50 ml of water and extracted with water/TBME. The organic phases are collected and dried over sodium sulphate, and the solvent is distilled off under reduced pressure on a rotary evaporator. The crude product is purified by chromatography (silica gel 60; eluent=1:1 heptane/ethyl acetate). The desired product is obtained in the form of white crystals in a yield of 76%.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([OH:20])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([O:20][C:35](=[O:37])[CH3:36])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OC(C)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 0.026 g (0.057 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidine (diastereomer 2, Example 18), 0.027 mL (0.28 mmol) of acetic anhydride, 0.046 mL of pyridine and 3.4 mg of DMAP in 2 mL of THF was stirred at rt for 18 h. The reaction mixture was concentrated and purified by chromatography (silica, hexanes:ethylacetate:(2N NH3 in MeOH), 15:15:1) to give the title compound as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].B(Cl)(Cl)Cl.C(Cl)Cl.Cl[CH2:18][C:19]#N.[Cl-].[Al+3].[Cl-].[Cl-].[BH4-].[Na+]>ClCCCl>[CH3:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[NH:4][CH:19]=[CH:18]2
Reactant: Cc1ccc(N)c(Br)c1
Reactant: N#CCCl
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [BH4-]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(Br)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
2-Bromo-4-methyl-aniline (10.0 g, 53.7 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 60 mL, 60 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (10 mL, 64.4 mmol) and aluminum chloride (10 g, 59.8 mmol) added, followed by 1,2-dichloroethane (70 mL). The reaction mixture was heated to 70° C. to distill off methylene chloride, and then refluxed for 24 hrs. The mixture was cooled to 0–5° C., treated with 25 M HCl (96 mL) at 0˜5° C. carefully, and then heated to 80° C. for 1 h until all solids dissolved. The aqueous layer was separated and extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (sodium sulfate) and concentrated a yellow solid (11.6 g, 82.3%), that was used without-further purification. The crude product was taken into dioxane (76 mL) and water (8.5 mL), and treated with sodium borohydride (1.75 g, 46.3 mmol) in portions. After 30 min at room temperature, all the starting material was consumed, and the reaction mixture was heated to reflux for 14 h. The mixture was then cooled to room temperature, treated with 0.1 N HCl (74 mL), and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 5-methyl-7-bromoindole (8.0 g, 90%). 1H NMR (400 MHz, CDCl3) 2.43 (s, 3H), 6.54 (dd, J1=1.94 Hz, J2=3.13 Hz, 1H), 7.20 (d, J=0.78 Hz, 1H), 7.22 (m, 1H), 7.36 (m, 1H), 8.22 (br, 1H); MS (ES, m/z): C9H8BrN: 210 (M+(79Br)+1), 212.0 (M+(81Br)+1).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[O:22][CH3:23])=[C:16]([CH3:25])[CH:15]=1.[Cl:26][CH:27]([CH3:31])[C:28](Cl)=[O:29].O>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([C:21]([O:22][CH3:23])=[O:24])[C:28](=[O:29])[CH:27]([Cl:26])[CH3:31])=[C:16]([CH3:25])[CH:15]=1
Reactant: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Reactant: CC(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(C(=O)C(C)Cl)c1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
18 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 100 mg of methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]carbamate (prepared as described in Example 22 above) in 4 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred for 15 minutes at the same temperature, after which 0.059 mi of 2-chloropropionyl chloride were added. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 3 hours. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The resulting.; residue was purified by preparative thin layer chromatography using a 1:1 by volume mixture of hexane and ethyl acetate to give 70 mg (yield 54%) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][NH:8][CH:4]([CH2:5]2)[CH2:3]1.Cl.Cl.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:3][C@@H:4]2[CH2:5][C@H:6]1[CH2:7][N:8]2[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]
Reactant: CN1CC2CC1CN2
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1N1C[C@@H]2C[C@H]1CN2C
Temperature: 25 °C
Yield: 81.7 %

Procedure:
(1S,4S)-2-Methyl-2,5-diazabicyclo[2.2.1]heptane.2HBr (6 g, 21.89 mmol) (which can be prepared by similar methods as described in Braish, T. F et al., J. Org. Chem. (1990), Vol. 55, pp. 1684-1687), 2-fluoro-5-nitrotoluene (2.61 g, 16.82 mmol) and K2CO3 (10.57 g, 76.46 mmol) in 30 mL NMP were heated at 110° C. for 14 h while stirring. The reaction mixture was cooled to ambient temperature, poured onto ice-water and stirred until precipitate formation. The yellow solid formed was collected by filtration and washed with 15% EtOAc/hexanes to provide 2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-nitrotoluene (3.4 g, 79%) in 98% purity; 1H NMR (DMSO-d6): δ 7.88-7.55 (m, 2H), 6.69 (d, 1H, J=8.8 Hz), 4.37 (s, 1H), 3.64 (dd, 1H, J=2.0 and 9.9 Hz), 3.38-3.55 (m, 2H), 2.81 (d, 1H, J=9.9 Hz), 2.65 (d, 1H, J=9.9 Hz), 2.33 (s, 3H), 2.23 (s, 3H), 1.87 (d, 1H, J=9.3 Hz), 1.75 (d, 1H, J=9.3 Hz); LCMS: purity: 98%; MS (m/e): 248 (MH+).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9](O)[C@H:8]([CH2:14][N:15]1[CH2:31][CH2:30][C:18]3([N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][NH:20][C:19]3=[O:29])[CH2:17][CH2:16]1)[CH2:7][CH2:6]2.C(O)(=O)C.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:14][N:15]1[CH2:31][CH2:30][C:18]3([N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][NH:20][C:19]3=[O:29])[CH2:17][CH2:16]1)[CH2:7][CH2:6]2
Reactant: O=C1NCN(c2ccccc2)C12CCN(C[C@@H]1CCc3cc(F)ccc3[C@H]1O)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1=Cc3ccc(F)cc3CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Finely-ground trans-8-[(6-fluoro-1,2,3,4-tetrahydro-1-hydroxy-2-naphthalenyl)methyl]-1-phenyl-1,3,8-triazaspiro[4.5]-decan-4-one (3g, see example 116) is added in small portions to a rapidly stirred acid solution comprising 20 ml acetic acid containing 20% v/v sulfuric acid maintained at 25° C. The resulting light-brown solution is stirred overnight at room temperature under nitrogen. The dehydration mixture is then gently warmed on a steam bath for 10 minutes. The warm solution is poured into ice-water (400 ml) and the resulting suspension basified with solid sodium bicarbonate. Extraction with chloroform yields a tan solid (1.9 g. 66%) containing small amounts of three impurities detected by TLC analysis. High pressure liquid chromatography (HPLC) of this material on silica gel with ethyl acetate gives 1.5 g of the free base of the title compound as colorless prisms, melting point 186°-187° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:13]CS([O-])(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[N:23]([CH2:13][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:19][CH:20]([CH3:22])[CH3:21])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)CC(CCS(=O)(=O)[O-])NC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CC(CN=[N+]=[N-])NC(=O)OCc1ccccc1

Procedure:
To the crude [2-(benzyloxycarbonylamino)-4-methyl-pentyl]methanesulfonate from the above reaction in DMF (50 mL), was added sodium azide 2.43 g. The reaction mixture was then heated to 85 degrees for 3 hrs. After cooling, ethyl acetate (300 mL) and water was added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum to afford the crude benzyl N-[1-(azidomethyl)-3-methyl-butyl]carbamate. To this crude intermediate was added THF (100 mL) followed by triphenylphosphine 7.21 g and stirred under nitrogen for 16 hrs. After addition of water (10 mL), and stirring for an additional 6 hrs, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columned using DCM/MeOH (0-10%) to afford benzyl N-[1-(aminomethyl)-3-methyl-butyl]carbamate (4.5 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]#[N:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][S:20][C:7]=12.[ClH:23].[OH-].[Na+]>O1CCCC1>[ClH:23].[ClH:23].[NH2:19][CH2:18][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2](=[O:1])[N:3]2[C:8]=1[C:7]1[S:20][CH:21]=[CH:22][C:6]=1[CH2:5][CH2:4]2
Reactant: N#Cc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Temperature: 25 °C

Procedure:
A solution of 1.5 g of 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carbonitrile in 15 ml of tetrahydrofuran was treated with 20 ml of a 1M BH3 /tetrahydrofuran solution and stirred at room temperature until the reaction was finished. The mixture was then acidified cautiously with 2N hydrochloric acid while cooling With ice, heated to boiling for a short time and made alkaline with 2N sodium hydroxide solution. The tetrahydrofuran was removed in vacuo and the aqueous residue was extracted with chloroform. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with chloroform/methanol (19:1). After treatment with methanolic hydrochloric acid, there was obtained pure 10-(aminomethyl)-4,5-dihydro-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one hydrochloride of m.p. 254°-255°.