Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:42]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][N:7]4[CH:11]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:9]=[C:8]4[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: O=C1CN(c2ccc(-c3nc(-c4ccc(Cl)cc4Cl)cn3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: O=C1CN(c2ccc(-c3nc(-c4ccc(Cl)cc4Cl)cn3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[1-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{4-[1-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [I-:1].C([O:4][C:5](=[O:15])[CH2:6][N:7]1[CH2:12][CH2:11][N+:10]([CH3:14])([CH3:13])[CH2:9][CH2:8]1)C>O>[I-:1].[C:5]([CH2:6][N:7]1[CH2:8][CH2:9][N+:10]([CH3:14])([CH3:13])[CH2:11][CH2:12]1)([OH:15])=[O:4]
Reactant: CCOC(=O)CN1CC[N+](C)(C)CC1
Agent: [I-]
Solvent: O
Product: C[N+]1(C)CCN(CC(=O)O)CC1
Yield: 50.9 %

Procedure:
11.77 g of 4-(2-ethoxy-2-oxoethyl)-1,1-dimethylpiperazinium iodide (22) was refluxed in 600 ml water for 48 h. The reaction mixture was evaporated to dryness and the product was crystallized with diethyl ether from ethanol. Yielded white powder 5.484 g (51%). 1H NMR at 300K (D2O): δ 3.30 (6H, s), 3.51 (4H, s), 3.69 (2H, s), 3.73 (4H, bm)
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1.[CH3:43][O:44][CH2:45][CH2:46][CH2:47][C:48](Cl)=[O:49]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:3]2[CH:39]=[CH:40][CH:41]=[CH:42][C:2]=2[NH:1][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][O:44][CH3:43])=[CH:17][CH:16]=1
Reactant: COCCCC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccccc2N)cc1
Product: COCCCC(=O)Nc1ccccc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Example 116b, 0.135 g of tert-butyl 3-(2-aminobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0034 g of 4-methoxybutyryl chloride are reacted. The title compound is obtained as a beige oil. Rf=0.10 (1:1 EtOAc-heptane); Rt=5.86.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(OCC)C>[Br:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]#[C:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCCCCCCC#Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Clc1ccc(C#CCCCCCCBr)cc1Cl
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
A solution of 8-(3,4-dichlorophenyl)-oct-7-yn-1-ol (0.52 g) in diethyl ether (2.5 ml) was treated with phosphorous tribromide (0.23 g) at 0° C. (ice/salt bath). The solution was stirred at 0-5° C. for 2 h and allowed to warm to room temperature. Aqueous sodium hydrogen carbonate solution was added. The aqueous layer was extracted with further diethyl ether (2×5 ml) and the combined organic layers were washed with brine (5 ml) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave an oil that was chromatographed on silica gel using dichloromethane as eluent. This gave 8-bromo-1-(3,4-dichlorophenyl)-1-octyne (0.25 g). 1H-NMR (CDCl3) δ 1.35-1.7 (6H, m), 1.75-1.95 (2H, m), 2.33 (2H, t), 3.35 (2H, t), 7.13 (1H, dd), 7.27 (1H, d) and 7.40 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C2C(COC([N:32]=[C:33]=[S:34])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:33](=[S:34])[NH2:32])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC1CCNCC1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CC1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of piperidin-4-ylacetic acid tert-butyl ester (10.72 g, 50.0 mmol) in chloroform (100 ml) was added to a solution of 9-fluorenylmethoxycarbonyl isothiocyanate (14.07 g, 50.0 mmol) in chloroform (100 ml) and the mixture was stirred at room temperature for 1 hour. Then, piperidine (80 ml) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, water was added, and it was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over magnesium sulfate and the residue obtained by vacuum concentration was washed with isopropyl ether and the title compound was obtained (11.35 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])CCC.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1.CCCCCC>[CH3:16][Si:15]([CH3:18])([CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: Cc1ccccc1Br
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccccc1[Si](C)(C)C
Temperature: -78 °C

Procedure:
In a 10 ml volume double neck flask substituted with argon gas, was laid 2 ml of a THF solution containing 0.32 mmol/L of o-bromotoluene obtained in the step 2 of Example 1, followed by cooling at −78° C. in an atmosphere of argon gas. To the solution, while stirring using a magnetic stirrer, 0.34 ml of a n-hexane containing 1.58 mol/L of n-butyl lithium was slowly drop wise added and stirred at −78° C. for 30 min. Subsequently, 0.59 ml of a THF solution containing 0.96 mmol/L of chlorotrimethylsilane was slowly drop wise added and stirred at −78° C. for 60 min. After reaction, the resulting solution was analyzed using GC (CBP column 1; 0.25 mm×25 m; starting temperature 50° C.; rate of temperature increase 10° C./min). As a result, o-trimethylsilyltoluene was obtained with a quantitative yield.
Reaction SMILES: [O:1]=[O+:2][O-].[C:4]([O:8][CH2:9]C)([CH3:7])([CH3:6])[CH3:5].[O:11]=[O+][O-].OO>C(OC)(C)(C)C>[CH:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:11].[OH:1][OH:2]
Reactant: CCOC(C)(C)C
Reactant: O=[O+][O-]
Agent: OO
Solvent: COC(C)(C)C
Product: CC(C)(C)OC=O

Procedure:
Referring to FIG. 12, primary and secondary reactions of MTBE with Ozone are shown. Karpel vel Leitner, R. N., A. L Papailhous, J. P. Crove, J. Payrot, and M. Dore (1994) “Oxidation of Methyl tert-Butyl Ether (MTBE) and Ethyl tert-Butyl Ether (ETBE) by Ozone and Combined Ozone/Hydrogen Peroxide” Ozone Science and Engineering 16, 41-54, described reaction pathways of ozone and MTBE in dilute aqueous solution using controlled experimental conditions. The primary reaction (90% of the consumed mass of MTBE) results in the formation of tert-butyl formate and hydrogen peroxide. A second parallel reaction (less than 10% of the consumed mass of MTBE) generates formaldehyde, TBA, and oxygen.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH:37]2[CH2:36][CH2:35][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:39][CH2:38]2)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(I)cc1[N+](=O)[O-]
Yield: 12.5 %

Procedure:
2.33 g (0.00795 mol) of 4-iodo-2-nitrobenzoic acid were boiled und reflux in 13.8 ml (0.16 mol) of oxalyl chloride for 3 hrs. After removal of the excess oxalyl chloride the mixture was concentrated twice with 30 ml of toluene each time. The residue was dissolved in 80 ml of toluene, treated with 1.94 ml (0.0139 mol) of triethylamine and 1.52 g (0.00795 mol) of 1-benzyl-4-hydroxypiperidine and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:3). 0.465 g (13%) of 1-benzyl-piperidin-4-yl 4-iodo-2-nitrobenzoate was obtained as a yellow oil. MS: me/e=467 (C19H20IN2O4 +).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[NH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])=[CH:26][CH:25]=[CH:24][CH:23]=2>C(#N)C>[CH2:2]([C:1]1[N:29]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=1)[CH2:3][CH3:4]
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C

Procedure:
Trimethyl orthobutyrate (1.90 g, 12.7 mmol) and pyridine hydrochloride (0.13 g, 1.2 mmol) were added to a suspension of 1-[(3-aminoquinolin-4-yl)amino]-2-methylpropan-2-ol (prepared as described in Part A of Example 8, approximately 2.7 g, 11.5 mmol) in acetonitrile (60 mL). The reaction mixture was heated at reflux for 45 minutes with a Dean Stark trap, then was allowed to cool to room temperature and was concentrated under reduced pressure. The crude product was subjected to flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to yield a mixture of compounds that were combined and resubjected to the reaction conditions. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure to afford 1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white solid that was used in the next step without purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][NH:30]C(OC(C)(C)C)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C.Cl>C(#N)C>[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][N:30]1[CH2:2][C:3]2[C:8](=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=2)[C:9]1=[O:11])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Agent: CN(C)C
Agent: Cl
Solvent: CC#N
Product: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CN1Cc2ccc([N+](=O)[O-])cc2C1=O

Procedure:
Methyl 6-bromomethyl-3-nitrobenzoate (430 mg, 1.64 mmol), N-glycyl-3(R)-methyl-β-alanine benzyl ester hydrochloride 2-4 (611 mg, 2.13 mmol) and trimethylamine (0.68 mL, 4.92 mmol) were stirred fin acetonitrile (10 mL) for 16 hours. The solution was poured into 1N HCl and extracted with EtOAc (3×), washed with brine, dried (MgSO4) and evaporated. Purification by column chromatography eluting with EtOAc afforded 2-6 as a solid. Rf (silica; EtOAc)=0.45. ##STR60## N-{[6-Amino-2,3-dihydro-1(1H)-isoindolone-2-yl]acetyl}-3(R)-methyl-β-alanine (2-7)
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:33]3[C:34]([C:37]#[N:38])=[CH:35][CH:36]=[C:32]3[C:12]3([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[O:11][C:10]=2[CH:39]=1)(=O)C.[Li+].[OH-].C1COCC1>CO>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:33]3[C:34]([C:37]#[N:38])=[CH:35][CH:36]=[C:32]3[C:12]3([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]4[CH:20]=[CH:21][C:22]([S:25]([CH:28]([CH3:29])[CH3:30])(=[O:27])=[O:26])=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)[O:11][C:10]=2[CH:39]=1
Reactant: CC(=O)OCc1ccc2c(c1)OC1(CCN(C(=O)c3ccc(S(=O)(=O)C(C)C)cc3)CC1)c1ccc(C#N)n1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2c(C#N)ccc23)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
(1-Cyano-1′-(4-(isopropylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-yl)methyl acetate (16.2 mg, 0.0297 mmol) was treated with 1M LiOH (1 mL), THF (5 mL) and MeOH (1 mL). The mixture was stirred at room temperature over night. The volatiles were removed and the residue was neutralized with 1N HCl. The mixture was extracted with CH2Cl2 (2×). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7′-(hydroxymethyl)-1-(4-isopropylsulfonylbenzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (11.3 mg, 75%). ESI-MS m/z calc. 505.58. found 506.5 (M+1)+; Retention time 1.49 minutes (3 min run). NMR (400 MHz, DMSO) δ 7.93 (dd, J=8.2, 6.5 Hz, 3H), 7.73 (d, J=8.3 Hz, 2H), 7.32 (d, J=4.0 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.45 (d, J=4.1 Hz, 1H), 5.39-5.30 (m, 1H), 4.51 (s, 2H), 3.81-3.64 (m, 1H), 3.54-3.42 (m, 2H), 3.41-3.37 (m, 1H), 2.20-2.12 (m, 1H), 2.13-2.03 (m, 1H), 2.01 (t, J=5.9 Hz, 1H), 1.57 (dd, J=12.5, 6.2 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])[S:6][CH:7]=1.[CH3:20][NH:21][C:22]1[C:27]([CH3:28])=[N:26][CH:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:21]([CH3:20])[C:22]2[C:27]([CH3:28])=[N:26][CH:25]=[CH:24][N:23]=2)[N:4]=1)=[O:10]
Reactant: CNc1nccnc1C
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1nccnc1N(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 80 °C

Procedure:
A CH2Cl2 (5 mL) suspension of 1-(4-(chloromethyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea (Intermediate XXI) (90 mg, 0.30 mmol), N,3-dimethylpyrazin-2-amine (69 mg, 0.56 mmol) and finely powdered K2CO3 (83 mg, 0.60 mmol) was evaporated to dryness. This mix was heated at 80° C. for 60 hours. Upon cooling, the organics were taken up in CH2Cl2 (3×5 mL) and the insolubles were removed by filtration. The volatiles were then removed in vacuo. The crude product was purified with chromatography (silica 1-4% MeOH in CH2Cl2) to afford the title compound. 1H NMR (400 MHz, CDCl3): 8.00 (s, 2H), 7.23 (m, 1H), 6.95 (m, 3H), 6.60 (s, 1H), 4.45 (d, 2H), 4.37 (s, 2H), 2.87 (s, 3H), 2.52 (s, 3H). MS (ES+): M/Z 387 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4]
Reactant: COC(=O)C1CC(N=[N+]=[N-])CN1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CC(N)CN1Cc1ccccc1
Reaction time: 6 h

Procedure:
To a solution of 4-azido-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester (9) in THF under N2 is added triphenylphosphine and water. The mixture is refluxed with stirring for about 6 h. After removal of THF, the residue is dissolved in Et2O, treated with HCl, stirred for 5 min, and extracted with Et2O. The aqueous solution is then treated with NaHCO3 and extracted, dried and concentrated to afford product 4-amino-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester (10).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:20][CH:19]4[NH:21][CH:15]([CH2:16][CH2:17][CH2:18]4)[CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C)C=O>[CH2:23]([N:21]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][N:13]([C:10]1[N:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=1)[CH2:14]2)[CH3:24]
Reactant: c1ccc(-c2ccc(N3CC4CCCC(C3)N4)nn2)cc1
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C2CCCC1CN(c1ccc(-c3ccccc3)nn1)C2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(6-phenyl-pyridazin-3-yl)-3,9-diaza-bicyclo[3.3.1]nonane free base (0.20 g, 0.71 mmol), bromoethane (0.059 ml, 0.78 mmol), N,N-diisopropylethylamine (0.18 g, 1.42 mmol) and dimethylformamide (5 ml) was stirred at 80° C. for 2 hours. Aqueous sodium hydroxide (20 ml, 1 M) was added and the mixture was extracted twice with diethylether (2×20 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as a crystalline solid. LC-ESI-HRMS of [M+H]+ shows 281.1761 Da. Calc. 281.176621 Da, dev. −1.9 ppm.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]1[CH:21]=[CH:20][C:10]2[N:11]3[CH2:19][CH2:18][CH2:17][C:12]3=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1.[OH2:22]>C(Cl)Cl>[O:15]=[S:14]1(=[O:16])[C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:9]=[C:8]([OH:22])[CH:7]=[CH:21][CH:20]=3)[CH:21]=[CH:20][C:10]=2[N:11]2[CH2:19][CH2:18][CH2:17][C:12]2=[N:13]1
Reactant: COc1ccc2c(c1)S(=O)(=O)N=C1CCCN12
Reactant: O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(O)c3)cc21
Reaction time: 24 h

Procedure:
A solution of 68.75 mmol of BBr3 in 25 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 27.50 mmol of 7-methoxy-2,3-dihydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide in 350 ml of methylene chloride. Stirring is carried out at ambient temperature for 24 hours. The reaction mixture is poured into a mixture of ice and water, and the suspension is stirred for 30 minutes. The precipitate is filtered off, rinsed several times with water, filtered under suction and dried in vacuo to yield the expected product.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][OH:18])([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]([CH2:17][O:18][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)([OH:16])[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCC1(O)CCN(Cc2ccccc2)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
60% sodium hydride (0.30 g) was added to a solution of the compound (1.66 g) obtained in Step 2 in anhydrous dimethylformamide (8 mL) under cooling with ice-water, and stirred at room temperature for thirty minutes under nitrogen atmosphere. 4-fluorobenzonitrile (0.91 g) was added to the mixture and stirred at room temperature for two days. The resulting mixture was poured into water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex NH™)(eluent; ethyl acetate:hexane=1:1) to obtain the titled compound (2.2 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[C:14]2[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][CH:7]=1)[CH:4]=[CH2:5].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:3]([C:6]1[C:14]2[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:7]=1)[CH:4]=[CH2:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CCc1c[nH]c2cccc(C(=O)OC)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1cn(S(=O)(=O)c2ccccc2)c2cccc(C(=O)OC)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a 0° C. cooled suspension of sodium hydride (60% dispersion in mineral oil, 0.450 g, 11.24 mmol) in DMF (50 mL) was slowly added a solution of methyl 3-allyl-1H-indole-4-carboxylate (2.20 g, 10.22 mmol) from Step A above in DMF (30 mL). The mixture stirred at 0° C. under an atmosphere of nitrogen for 1 h. To this was added benzenesulfonyl chloride (1.30 mL, 10.22 mmol). The mixture continued to stir for 16 h while gradually warming to room temperature. The mixture was carefully quenched with saturated aqueous ammonium chloride solution (300 mL) and the aqueous mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water (4×100 mL), brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) afforded methyl 3-allyl-1-(phenylsulfonyl)-1H-indole-4-carboxylate (3.15 g, 87%) as a pale yellow oil, which crystallized upon standing: 1H NMR (500 MHz, CDCl3) δ 8.19 (m, 1H), 7.85 (m, 2H), 7.63 (m, 1H), 7.55 (m, 1H), 7.44 (s, 1H), 7.41 (m, 2H), 7.32 (m, 2H), 5.96 (m, 1H), 5.07 (m, 1H), 4.97 (m, 1H), 3.89 (s, 3H), 3.54 (m, 2H): MS (ESI+) m/z 356 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1.[OH-:22].[Na+].Cl>>[NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c2nc(N)nc(Cl)c12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c2nc(N)[nH]c(=O)c12
Reaction time: 1 h

Procedure:
To the compound from Step B (157 mg, 0.50 mmol) was added NaOH (2M, aqueous) (2 mL). The resulting solution was stirred at relux for 1 h, cooled and neutralized by addition of HCl (2M, aqueous). The mixture was evaporated in vacuo and the crude product purified on silica using methanol/dichloromehane (2:8) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (53 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl.[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: SCc1ccccc1
Reactant: FC(Cl)=CCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(Cl)=CCCCCCSCc1ccccc1
Yield: 63.3 %

Procedure:
Operating as described in Example 10, from 3 g of 1,7-dichloro-1-fluoro-hept-1-ene, 2.14 g of benzylmercaptan, 0.7 g of NaH (at 55% concentration in paraffin oil) and 30 ml of N,N-dimethylformamide there were obtained 2.8 g of product which was purified in a chromatography column.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:6]1[C:5]2[C:10](=[CH:11][C:2]([I:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc(I)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2cc(I)ccc12

Procedure:
7-Iodoquinazolin-4-one (0.46 g) was treated with phosphorous oxychloride (5 ml) at reflux under nitrogen for 2 hours. The mixture was cooled, evaporated and partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic phase was dried and concentrated in vacuo to give the title compound (0.43 g); m/z (M+1+) 291.