Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C(OC=C)=O.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH:16]2[CH2:22][CH:21]3[N:23](C)[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)=[N:8]1>ClCCCl>[ClH:1].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH:16]2[CH2:22][CH:21]3[NH:23][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)=[N:8]1
Reactant: C=COC(=O)Cl
Reactant: CN1C2CCC1CC(c1noc3ccccc13)C2
Solvent: ClCCCl
Product: Cl
Product: c1ccc2c(C3CC4CCC(C3)N4)noc2c1

Procedure:
Vinyl chloroformate (3.6 g) was added dropwise to a solution of 3-(1,2-benzisoxazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane (6.0 g) in 125 ml of 1,2-dichloroethane at 0° C. The resulting suspension was heated at reflux for 3 hours, the solution was cooled, and the solvent was removed in vacuo. The residue was suspended in 125 ml of ethanol and acidified with HCl in isopropanol (to about a pH of 1), and the mixture was heated at reflux for 2 hours. The mixture was cooled, and 3.9 g of 3-( 1,2-benzisoxazol-3-yl)-8-azabicyclo[3.2.1 ]octane hydrochloride crystallized, m.p. 264°-268° C.
Reaction SMILES: Br[C:2]#[N:3].N1C=CN=C1.[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:21][NH2:22])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>C(Cl)Cl.C1COCC1>[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[O:20][C:2]([NH2:3])=[N:22][N:21]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: N#CBr
Reactant: NNC(=O)c1ccc2cnccc2c1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1nnc(-c2ccc3cnccc3c2)o1
Yield: 95.1 %

Procedure:
A 3 M DCM solution of bromoformonitrile (0.2 mL, 0.6 mmol) (commercially available from Aldrich) was mixed with imidazole (0.157 g, 2.3 mmol) (commercially available from Aldrich) in 10 mL DCM. The mixture was heated and maintained to reflux for 30 minutes in a round bottom flask. After the DCM was removed under a reduced pressure, isoquinoline-6-carbohydrazide (0.1 g, 0.53 mmol) suspended in 50 mL THF was added into the flask. The mixture was heated and maintained at reflux for 3 hours. After removing the THF, the remaining residue was mixed with 10 mL water and filtered. After washing with water and air drying, a white solid was obtained as the desired product (0.107 g, 96%) LCMS (API-ES) m/z (%): 213.0 (100%, M++H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([S:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([CH3:16])=[N:10]2.CO.[OH-].[Li+]>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:26])=[O:2])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:16])[C:8]([S:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:7]2[CH3:25]
Reactant: COC(=O)Cc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c(Cl)ccc(CC(=O)O)c2c(C)c1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of [8-chloro-3-(4-chlorophenylsulfanyl)-2,4-dimethylquinolin-5-yl]acetic acid methyl ester (0.040 g), methanol (2.0 mL), water (0.4 mL) and saturated aqueous lithium hydroxide solution (0.2 mL) was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure and the residue diluted with water (2.0 mL) and then the pH adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a grey-brown solid, 0.038 g.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[F:19][C:20]1[CH:27]=[C:26]([O:28][CH:29]([F:31])[F:30])[CH:25]=[C:24]([F:32])[C:21]=1[CH2:22][OH:23]>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:23][CH2:22][C:21]1[C:20]([F:19])=[CH:27][C:26]([O:28][CH:29]([F:30])[F:31])=[CH:25][C:24]=1[F:32])=[O:3]
Reactant: OCc1c(F)cc(OC(F)F)cc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1c(F)cc(OC(F)F)cc1F
Product: Cl

Procedure:
2,6-Difluoro-4-difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2,6-difluoro-4-difluoromethoxybenzyl alcohol according to the method described for Example 54 to give the product as a, white solid (0.1406 g, 65% overall); νmax (nujol)/cm−1 3342, 1684, 1640, 1599, 1378, 1308, 1166, and 1089; δH (400 MHz, DMSO-d6) 9.69 (2H, br), 7.38 (1H, t, J 73 Hz), 7.15–7.10 (2H, m), 5.14 (2H, s), 4.24 (2H, m), 3.13 (2H, d, J 13 Hz), 3.05 (2H, dd, J 5.2 and 13 Hz), and 1.27 (6H, d, J 7.2 Hz).
Reaction SMILES: O.[OH-].[Li+].[CH:4]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][O:6][C:5]=1[CH2:12][OH:13].S(OCC)(O[CH2:18][CH3:19])(=O)=O.Cl>O>[CH3:18][CH2:19][O:13][CH2:12][C:5]1[O:6][CH:7]=[C:8]([OH:11])[C:9](=[O:10])[CH:4]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: O=c1cc(CO)occ1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOCc1cc(=O)c(O)co1
Reaction time: 0.33 h

Procedure:
60 ml of water was put in a 100 ml-Erlenmeyer flask, and 10.07 g (0.24 mol) of lithium hydroxide monohydrate and then 11.37 g (0.08 mol) of kojic acid were added thereto and dissolved with stirring. While the temperature of the resulting solution was kept at 40 to 45° C., 14.80 g (0.096 mol) of diethyl sulfate was dropwise added thereto over a period of 20 minutes. Afterwards, the whole was stirred for a further 30 minutes at the same temperature and then overnight at room temperature. The pH of the reaction mixture was adjusted to 6.0 by 1N hydrochloric acid. Water was removed from the reaction mixture using an evaporator by distillation under reduced pressure, and the remaining reddish brown viscous liquid was extracted three times each with 70 ml of a hot benzene. The resulting extract was dewatered by adding anhydrous magnesium sulfate thereto, and then filtered. Benzene was removed from the resulting filtrate using an evaporator by distillation under reduced pressure. The remaining yellowish brown viscous liquid was cooled to solidify (Crude yield: 3.67 g (27%), m.p. 68 to 70° C.). The yellowish brown solid was recrystallized three times from di-isopropyl ether using active carbons to obtain a pure white crystal of 2-ethoxymethyl-5-hydroxy-γ-pyrone.
Reaction SMILES: C(OC(=O)C(CC)[CH2:6][CH2:7][N:8]1[C:25](=[S:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:27])C.N(C[CH2:35][CH2:36][O:37][CH3:38])=C=S.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:36]([O:37][C:9]([C:10]1[NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:15][C:16]=2[CH:17]=1)=[O:27])[CH3:35].[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:15][C:16]3[CH:17]=[C:10]4[C:9](=[O:27])[N:8]([CH2:7][CH2:6][CH2:36][O:37][CH3:38])[C:25](=[S:26])[N:11]4[C:12]=3[CH:13]=2)=[CH:19][CH:20]=1
Reactant: COCCCN=C=S
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2oc(-c3ccc(Cl)cc3)cc2[nH]1
Product: COCCCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Temperature: 120 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
2-(4-Chloro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (29 mg, 0.1 mmol) was prepared as described hereinabove (see, preparation of Compound 4), and placed in a heavy-walled glass tube with a threaded Teflon plug. 1-Isothiocyanato-3-methoxy-propane (131 mg, 1. mmol, 10 molequivalents) and triethylamine (202 mg, 2 mmol, 20 molequivalents) were added thereto, the tube was sealed and the mixture was heated while stirring at 120° C. for 6 hours. The mixture was then cooled to room temperature, dissolved in chloroform and the solvents were evaporated under reduced pressure. The crude residue was dissolved in dichloromethane and was purified by column chromatography using a 95:5 hexane:ethyl acetate mixture as eluent, to give Compound 28 (13 mg, 35% yield) as an orange solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[C:15](=[O:44])[CH:16]([CH2:19][C:20]3[N:21]=[CH:22][N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:24]=3)[CH2:17][CH2:18][C:7]=12>O>[NH:23]1[CH:24]=[C:20]([CH2:19][CH:16]2[C:15](=[O:44])[N:8]3[C:9]4[C:14]([C:6]([CH3:5])=[C:7]3[CH2:18][CH2:17]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:21]=[CH:22]1
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn1)CC2
Solvent: CC(=O)O
Solvent: O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cc1c[nH]cn1)CC2
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a mixture of acetic acid (50 ml) and water (15 ml), was added 8,9-dihydro-10-methyl-7-[(1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (4.93 g), and stirred at 60° C. for 2 hours. After being cooled, the precipitates were filtered off. The filtrate was neutralized with aqueous 8N-sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was crystallized from diisopropyl ether-ethyl acetate (5:1, V/V) to give 8,9-dihydro-7-[(1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.84 g).
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][C:7](=[O:9])[CH3:8])[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]12.NC(N)=O.[Br:20]Br>CO>[Br:20][CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:4](=[O:10])[C:3]2[C:2](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]1=[O:15]
Reactant: BrBr
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: NC(N)=O
Solvent: CO
Product: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
To a solution of phthalimidoacetone (4.04 g, 19.9 mmol) in methanol (100 mL) was added urea (1.19 g, 19.9 mmol) and bromine (3.18 g, 19.9 mmol) and the resulting solution was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue taken up in DCM (150 mL) and water (50 mL). The layers were separated and the organic layer was dried, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/hexanes=0/100→50/50) to give 159 mg (3% yield) of the title compound. 1H NMR (300 MHz, CDCl3) δ: 7.90-7.86 (m, 2H), 7.79-7.73 (m, 2H), 4.78 (s, 2H), 4.01 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[C:30](F)=[CH:31][C:32]([F:51])=[C:33]([S:35]([N:38]([C:46]2[N:47]=[CH:48][S:49][CH:50]=2)[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:37])=[O:36])[CH:34]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.C(OCC)(=O)C.O>[C:41]([O:40][C:39]([N:38]([C:46]1[N:47]=[CH:48][S:49][CH:50]=1)[S:35]([C:33]1[C:32]([F:51])=[CH:31][C:30]([O:21][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)=[C:29]([Cl:28])[CH:34]=1)(=[O:37])=[O:36])=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c3cscn3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Example 655 from above can be made as follows. To a solution of tert-butyl 4-(5-chloro-2-hydroxyphenyl)piperidine-1-carboxylate (Preparation 231, 38 mg, 0.122 mmol) and potassium carbonate (50.6 mg, 0.366 mmol) in dimethyl sulfoxide (1 mL) was added tert-butyl [(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 453, 50 mg, 0.122 mmol). The mixture was stirred at room temperature for 16 hours before diluting with ethyl acetate (10 mL) and water (10 mL). The aqueous phase was acidified to pH 4 with saturated citric acid solution (aqueous) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford tert-butyl 4-[2-(4-{[(tert-butoxycarbonyl)(1,3-thiazol-4-yl)amino]sulfonyl}-2-chloro-5-fluorophenoxy)-5-chlorophenyl]piperidine-1-carboxylate as a white foam. This was dissolved in dichloromethane (1 mL), trifluoroacetic acid added (200 μL) and reaction stirred for 16 hours at room temperature before concentrating in vacuo. Purification by preparative HPLC afforded the title compound.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]([C:8]3[O:12][N:11]=[C:10]([NH2:13])[N:9]=3)[CH2:7][N:3](C2)[CH2:2]1.F[C:15](F)(F)[C:16](O)=O.[CH3:21][CH:22](O)[CH3:23].[O:25]=[C:26]([C:28](=[O:30])[OH:29])[OH:27]>ClCCl.ClCCl.CO>[C:28]([OH:30])(=[O:29])[C:26]([OH:27])=[O:25].[CH2:21]([N:13]([CH2:26][C:15]#[CH:16])[C:10]1[N:9]=[C:8]([C:6]2[CH2:7][NH:3][CH2:2][CH2:1][CH:5]=2)[O:12][N:11]=1)[C:22]#[CH:23]
Reactant: Nc1noc(C2CN3CCC2C3)n1
Reactant: CC(C)O
Reactant: O=C(O)C(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: C#CCN(CC#C)c1noc(C2=CCCNC2)n1

Procedure:
The foregoing oxadiazole (135 mg, 0.00039 mol) was stirred with trifluoroacetic acid (0.18 mL, 0.0024 mol) in dichloromethane (6 mL) for 24 hours. The hydrogen oxalate salt had mp 134°-135° C. (propan-2-ol). Rf=0.78 in dichloromethane/methanol (9:1) on alumina plates. Mass Spectrum, m/z 242 for M+ of free base. (Found: C, 53.87; H, 4.90; N, 16.52. C13H14N4O. C2H2O4 requires C, 54.21; H, 4.85; N, 16.86%).
Reaction SMILES: C([O:5][C:6](=[O:16])[C@@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.C(N(CC)CC)C.[Cl:24][C:25]1[C:26]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:27]=2[S:28][C:29]=1[C:30](Cl)=[O:31]>ClCCl>[Cl:24][C:25]1[C:26]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:27]=2[S:28][C:29]=1[C:30]([NH:8][C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:16])=[O:31]
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Reactant: O=C(Cl)c1sc2cc(C(F)(F)F)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general method B, to a solution of A1 (55.33 mg, 0.25 mmol) in dry dichloromethane (2 mL) at 0° C. was added triethylamine (0.043 mL, 0.28 mmol) and 5 (74.78 mg, 0.25 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. Then dissolved the oil mixture in 2 mL CH2Cl2 and 2 mL TFA was add under argon. The reaction mixture was stirred at room temperature for 12 h (TLC monitor). The solvent was removed under reduce pressure and the crude compound was purified by flash chromatography on silica gel, using HOAc/ethyl acetate (1:100) as the eluent, gave 5a; (100.64 mg, 94.1%). [α]D25: −21.1 (c=0.30, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 8.12 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.71-7.61 (m, 2H), 7.37-7.26 (m, 5H), 6.83 (s, 1H), 5.17-5.15 (m, 1H), 3.45-3.30 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 175.31, 160.07, 139.09, 137.76, 135.24, 135.13, 129.90, 129.46, 128.84, 127.56, 125.63, 123.89, 122.16, 120.45, 120.40, 119.49, 54.09, 39.26, 29.70; HRMS (ESI): calcd for: C19H13ClF3NO3S [M−H]−=426.0184, obsd [M−H]−=426.0170.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[H-].[Na+].[CH3:18][C:19]([CH3:21])=O>C(COC)OC.O>[CH2:2]([O:3][C:4](=[O:5])[C:6]([F:7])=[C:19]([CH3:21])[CH3:18])[CH3:1]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(F)=C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
Triethyl 2-fluoro-2-phosphonoacetate (20 g, 82.6 mmol) (Aldrich) was added dropwise to a stirred solution of sodium hydride (3.6 g, 90.8 mmol) in dimethoxyethane (100 mL) at 0° C. After stirring at room temperature for 20 min, acetone (4.78 g, 82.6 mmol) was added and the reaction mixture was refluxed for overnight. The two phase mixture was cooled, diluted with water and extracted with ether. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified with chromatography (Hexanes) to give 2-fluoro-3-methyl-but-2-enoic acid ethyl ester as colorless oil (Yield: 9.0 g, 61.6%).
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>C(#N)C>[N:1]1([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][S:17](=[O:20])(=[O:19])[NH2:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCCOc1ccc(-n2ccnc2)cc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Product: NS(=O)(=O)OCCCOc1ccc(-n2ccnc2)cc1
Reaction time: 20 h
Yield: 43 %

Procedure:
A solution of 9.0 g (0.041 mole) of 3-[4-(1H-imidazol-1-yl)phenoxy]-1-propanol in 150 ml of acetonitrile was treated with a solution of one equivalent of sulfamoyl chloride in 13 ml of acetonitrile. The mixture was stirred for 20 hr. The reaction mixture was concentrated under vacuum and the residue was dissolved in water. The aqueous solution was filtered and the filtrate was basified to pH 8 with potassium carbonate. The mixture was extracted with ethyl acetate. The organic fraction was concentrated under a stream of nitrogen and the precipitate was collected and dried to give 5.2 g (43%) of the title compound as a tan powder, mp 105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]([NH:8][C:9]2[O:10][C@:11]3([CH2:19][N:20]=2)[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]3)=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]([NH:8][C:9]2[O:10][C@:11]3([CH2:19][N:20]=2)[CH:16]2[CH2:17][CH2:18][N+:13]([O-:30])([CH2:14][CH2:15]2)[CH2:12]3)=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ncc1Cl
Solvent: C1CCOC1
Product: Cc1cc(NC2=NC[C@@]3(C[N+]4([O-])CCC3CC4)O2)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To (R)—N-(5-Chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.04 g, 0.13 mmol) in THF (10 mL) was added m-CPBA (0.025 g, 0.14 mmol). The reaction stirred at room temperature for 2 hours and was then concentrated to a crude powder. The product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (S)-2-(5-chloro-4-methylpyridin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.019 g, 0.06 mmol, 44% yield) as a white powder. 1H NMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 6.75-7.09 (m, 1H), 4.00 (d, J=10.4 Hz, 1H), 3.84 (d, J=10.4 Hz, 1H), 3.61-3.78 (m, 2H), 3.41-3.54 (m, 3H), 3.23-3.38 (m, 3H), 2.45 (br. s., 1H), 2.25-2.38 (m, 4H), 1.88-2.22 (m, 1H). MS (LC/MS) R.T.=0.91; [M+H]+=323.11.
Reaction SMILES: [C:1]([CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1)#[N:2].Cl[C:30]([O:32][CH3:33])=[O:31]>CC#N>[C:1]([C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][N:5]([C:30]([O:32][CH3:33])=[O:31])[CH2:4]1)#[N:2]
Reactant: COc1ccc(C2CN(Cc3ccccc3)CC2C#N)cc1OC1CCCC1
Reactant: COC(=O)Cl
Solvent: CC#N
Product: COC(=O)N1C[C@@H](C#N)[C@H](c2ccc(OC)c(OC3CCCC3)c2)C1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
To a solution of 3-cyano-4-(3-cyclopentoxy-4-methoxyphenyl)-1-(phenylmethyl)pyrrolidine (300 mg, 0.79 mmol) in 2 mL of CH3CN in a thick-walled glass sealable tube was added methyl chloroformate (300 mg, 3.19 mmol). The tube was sealed and the resulting solution was heated to 80° C. for 12 hr. After cooling to room temperature, the solution was concentrated. Silica gel chromatography of the residue (2:1, hexanes:ethyl acetate) provided trans-3-cyano-4-(3-cyclopentoxy-4-methoxyphenyl)-1-(methoxycarbonyl)pyrrolidine as a white solid (233 mg, 85%), m.p. 101°-104° C. Anal. Calcd for C19H24N2O4 : C, 66.26; H, 7.02; N, 8.13. Found: C, 66.14; H, 7.06; N, 8.10.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH3:13])[CH:10]=[CH:9]2.Cl.Cl.[CH3:16][N:17]1[CH2:23][C:22]2[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:26]=[N:27][C:21]=2[NH:20][C:19](=[O:33])[CH2:18]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH3:13])[CH:10]=[CH:9]2)[C:30](=[O:31])/[CH:29]=[CH:28]/[C:25]1[CH:26]=[N:27][C:21]2[NH:20][C:19](=[O:33])[CH2:18][N:17]([CH3:16])[CH2:23][C:22]=2[CH:24]=1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CNCc1cccc2ccn(C)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3cccc4ccn(C)c34)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of (methyl-(1-methyl-1H-indol-7-ylmethyl)amine (103 mg, 0.6 mmol), (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid dihydrochloride (160 mg, 0.5 mmol), HOBt (81 mg, 0.5 mmol) and diisopropylethylamine (0.41 mL, 2 mmol) in DMF (12 mL) was added EDC hydrochloride (114 mg, 0.6 mmol). The mixture was stirred overnight at room temperature. Water (75 mL) was added and the solution stirred for 1 hr. The precipitate was collected by filtration and triturated with hexanes to afford (E)-N-methyl-N-(1-methylindol-7-ylmethyl)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (100 mg, 50%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (m, 1H), 8.54-8.47 (m, 1H), 8.16-7.97 (m, 1H), 7.62-7.19 (m, 4H), 6.92-6.97 (m, 1H), 6.78-6.58 (m, 1H), 6.39 (d, J=3.1 Hz, 1H) 5.48-5.19 (2×s, 2H), 3.99-4.11 (2×s, 3H), 3.79-3.70 (2×s, 2H), 3.42-3.36 (m, 2H), 3.30-3.13 (2×s, 3H), 2.36-2.30 (2×s, 3H); ESI MS m/z 404 [C23H25N5O2+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.CN1C[CH2:21][O:20]CC1.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25].C1C[O:34]CC1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[CH2:27]([O:26][C:24]([O:34][C:21]([O:13][CH2:11][CH:10]([CH3:9])[CH3:14])=[O:20])=[O:25])[CH:28]([CH3:30])[CH3:29]
Reactant: C1CCOC1
Reactant: CN1CCOCC1
Reactant: CC(C)COC(=O)Cl
Agent: O=C(O)c1ccc(-c2ccccn2)cc1
Product: CC(C)COC(=O)OC(=O)OCC(C)C

Procedure:
With the exclusion of air, 6.0 g (30 mmol) of 4-(pyridin-2-yl)-benzoic acid are suspended at -20° C. in 90 ml of THF, and 9.90 ml (90 mmol) of N-methyl-morpholine and 4.32 ml (33 mmol) of isobutyl chloroformate are added. After 30 min the mixture is filtered and washed with a small amount of cold THF; the filtrate is partially concentrated by evaporation and the residue is diluted with methylene chloride, washed with ice-water and cold brine, dried (Na2SO4) and concentrated by evaporation to yield the title compound: 1H-NMR (CDCl3) inter alia 8.75 (m, 1H), 8.16 (AB, J=8, 4H), 7.81 (m, 2H), 7.32 (4-line system, J=5, 1H), 4.16 (d, J=7, 2H), 2.10 (9-line system, J=7, 1H), 1.02 (d, J=7, 6H).