Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C@H:23]([CH2:35][OH:36])[CH2:24][CH2:25][N:26]3[CH2:33][CH2:32][C:29]4([CH2:31][CH2:30]4)[C@H:28]([OH:34])[CH2:27]3)[C:19](=[O:37])[C@@H:18]2[CH3:38])=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(NCC)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[O:36][CH2:35][C@@H:23]([N:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[NH:14][C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[C@@H:18]([CH3:38])[C:19]1=[O:37])[CH2:24][CH2:25][N:26]1[CH2:33][CH2:32][C:29]2([CH2:31][CH2:30]2)[C@H:28]([OH:34])[CH2:27]1
Reactant: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCNCC
Product: COC(=O)OC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(Cl)c(Cl)c2)[C@@H](C)C1=O
Temperature: 0 °C
Yield: 93.3 %

Procedure:
Methyl chloroformate (9 mg, 0.1 mmol) was added at 0° C. to a solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide (example 106; 50 mg, 0.10 mmol) in dichloromethane (1 mL). The ice bath was removed, then after 30 min the reaction mixture was cooled to 0° C., treated with diethylamine (4 mg, 50 μmol), and evaporated. Chromatography (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) provided the title compound (52 mg, 93%). White solid, MS (ISP)=557.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:15](Cl)(Cl)(=[O:17])=[O:16].[NH3:20]>>[C:1]1([C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][S:15]([NH2:20])(=[O:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=S(=O)(Cl)Cl
Reactant: C=C(c1ccccc1)c1ccccc1
Product: NS(=O)(=O)C=C(c1ccccc1)c1ccccc1

Procedure:
When 1,1-diphenylethene reacts with sulfuryl chloride in N,N-dimethylformaide, followed by treatment with ammonia, according to the procedure of Preparation A, there is obtained 2,2-diphenylethenesulfonamide, m.p. 134°-135°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[S:27]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:29])=[O:28]>C(Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][S:27]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:29])=[O:28])=[CH:3][C:4]=1[NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)NCCS(=O)(=O)Cl
Reactant: Cc1cc(C)nc(Nc2cc(N)cnc2C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCNC(=O)OC(C)(C)C)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-amino-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (PrepEx 1.8) (150 mg, 0.63 mmol) in DCM (5 mL) was added triethylamine (0.26 mL, 1.88 mmol) followed by the dropwise addition of tert-butyl [2-(chlorosulfonyl)ethyl]carbamate (25% w/w in DCM, 920 mg, 0.94 mmol). The reaction mixture was stirred for 3 hours at room temperature. Additional tert-butyl [2-(chlorosulfonyl)ethyl]carbamate (25% w/w in DCM, 920 mg, 0.94 mmol) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organics were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford tert-butyl [2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}sulfamoyl)ethyl]carbamate. MS ESI calc'd. for C20H27N6O4S [M+H]+ 447. found 447. 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.01 (s, 1H), 6.86 (t, J=5.5 Hz, 1H), 6.73 (s, 1H), 6.65 (s, 1H), 3.41 (t, J=6.7 Hz, 2H), 3.32-3.29 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2Cl)([O-:18])=[O:17].O>O1CCCC1>[N+:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[O:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)(C)c1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCOc2ncnc3ccc([N+](=O)[O-])cc23)cc1

Procedure:
2-(4-tert-butylphenyl)ethanol (1.0 g, 5.59 mmol) is dissolved in dry tetrahydrofuran (7 ml) and to it is added sodium hydride (48.5 mg, 2.02 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 6-Nitro-4-chloroquinazoline (1.17 g, 5.6 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH2:21]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][N:34]([C:18](=[O:20])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCCN(C(=O)OCc2ccccc2)CC1
Yield: 97.7 %

Procedure:
15.29 g of N-tert-butoxycarbonyltyrosine and 12.73 g of N-benzyloxycarbonylhomopiperazine were dissolved in 280 ml of tetrahydrofuran, to the solution were added 8.09 g of 1-hydroxybenzotriazole hydrate and 11.77 g of DCC at a room temperature with stirring, and the reaction mixture was stirred for 16 hours. The reaction mixture was evaporated to remove the solvent under a reduced pressure, to the residue was added benzene, and insoluble matter was filtered by suction and washed with benzene. The benzene layers were combined and evaporated off under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (100:1), to obtain 26.42 g of the title compound in colorless amorphous form.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.[CH:25]([C:28]([C:30]1[N:31]=[CH:32][N:33]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=1)=[O:29])([CH3:27])[CH3:26].O>C1COCC1.CCCCCC>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:28]([C:30]1[N:31]=[CH:32][N:33]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]=1)([OH:29])[CH:25]([CH3:27])[CH3:26])[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
6-Bromo-2-tert-butyldimethylsilyloxynaphthalene (60.0 g) was dissolved in THF (600 mL) and the solution was cooled to −70° C. A solution (1.6 M: 111 mL) of n-butyllithium in hexane was slowly added dropwise and the mixture was stirred for 30 min. Then a solution (200 mL) of isopropyl(1-trityl-1H-imidazol-4-yl)ketone (52.1 g) in THF was added dropwise. The mixture was stirred at −70° C. for 30 min. and water was added to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to give the title compound (79.5 g) as a colorless powder.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7](=[N:20][CH:21]1[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C>C1COCC1.CC(O)C>[C:7](=[N:20][C:21]1([CH2:3][C:2]#[CH:1])[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCC(N=C(c2ccccc2)c2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCN(C)C1=O
Reaction time: 2 h

Procedure:
Potassium tert-butoxide 1.7M in THF (32.8 mL, 55.76 mmol) was added dropwise over a period of 80 minutes (by syringe pump) to a solution of the 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (14.11 g, 50.692 mmol) (which may be prepared as described in Description 1) and propargyl bromide (6.78 mL, 60.83 mmol) in THF (250 mL) at 0° C. under nitrogen. The reaction was stirred for 2 hours. Additional KOtBu (5 ml) was added dropwise and stirring was continued for 15 mins. The reaction was quenched by the addition of satd. aq. NaHCO3 and diluted with EtOAc. The phases were separated, the organic layer was dried (Na2SO4) and the solvent evaporated to afford a crude brown oil which solidified on standing. This waxy-solid was suspended in IPA (approx. 30 ml) and stirred for 1 hr. The solid was filtered off, washed with a little IPA to afford 3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D2) as a light brown solid (6.26 g);
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:21]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:4][C:5]([N:8]([CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)[CH3:9])=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:21]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:4][C:5]([N:8]([CH3:9])[CH2:10][CH2:11][NH:12][CH3:13])=[N:6][CH:7]=1
Reactant: CN(CCN(C)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCN(C)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 1 h

Procedure:
In methylene chloride (2.0 ml) was dissolved tert-butyl 2-[N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine-2-yl]-N-methylamino]ethyl-methylcarbamate (61 mg, 0.10 mmol), followed by the addition of anisole (40 μl) and trifluoroacetic acid (200 μl) at room temperature. The resulting mixture was stirred for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel chromatography (3% methanol/chloroform→3% methanol, 3% tertbutylamine/chloroform), whereby the title compound (21 mg, 41%) was obtained as an oil.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH2:8][C:7](=O)[N:6]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[F:19])[C:5]2=[O:20])[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:23])=O.CN(C)C1C=CC=CC=1>O>[Cl:23][C:7]1[N:6]([C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:5](=[O:20])[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:9](=[O:10])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(=O)N(C2CC2)C(=O)N1c1ccc(I)cc1F
Solvent: O
Solvent: CN(C)c1ccccc1
Product: O=c1cc(Cl)n(-c2ccc(I)cc2F)c(=O)n1C1CC1
Temperature: 110 °C

Procedure:
To 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-pyrimidine-2,4,6-trione 49 (59.0 g) obtained in Step 2 were added phosphorus oxychloride (85.0 ml) and dimethylaniline (29.0 ml), and water (8.3 ml) was added dropwise to the mixture at room temperature with stirring. After the completion of the dropwise addition, the mixture was stirred with heating at 110° C. for 1 hr. After allowing to cool to room temperature, the reaction mixture was added dropwise to ice water-toluene [2:1 (volume ratio), 900 ml] with stirring. The mixture was stirred at room temperature for 1 hr. The organic layer was separated, and washed successively with water (300 ml) and brine (300 ml). Anhydrous magnesium sulfate and activated carbon were added and the mixture was stirred. Anhydrous magnesium sulfate and activated carbon were filtered off, and the filtrate was concentrated under reduced pressure to give a 1:2 mixture (62.9 g) of 6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 50 and 6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 51 as a yellow foamy oil, which was used for the next step without purification.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21

Procedure:
1-Ethyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 5 but starting from 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.5 g of 4-methylpiperazine in 16 cm3 of pyridine After recrystallizing 4 times from, in total, 120 cm3 of dimethylformamide, 1.2 g of 1-ethyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 285°-286° C. solvated by 1% of water.
Reaction SMILES: CC(C1C=CC(C2CCCNC2)=C(O)C=1)(C)CCCCCC.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH3:33][C:34]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][CH:55]=[CH2:56])[CH2:49]2)=[C:44]([O:57]CC=C)[CH:43]=1)([CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(O)C>[CH3:41][C:34]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][CH:55]=[CH2:56])[CH2:49]2)=[C:44]([OH:57])[CH:43]=1)([CH3:33])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: C=CCOc1cc(C(C)(C)CCCCCC)ccc1C1CCCN(CC=C)C1
Agent: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C=CCBr
Product: C=CCN1CCCC(c2ccc(C(C)(C)CCCCCC)cc2O)C1
Yield: 40 %

Procedure:
A mixture of 900 mg. (2.97 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine, 481 mg. (3.48 mmoles) of anhydrous potassium carbonate and 359 mg. (2.97 mmoles) of allyl bromide in 20 ml. of ethanol is heated at reflux for 23 hours. The reaction mixture is concentrated under reduced pressure and the residue dissolved in 250 ml. of saturated sodium bicarbonate and 200 ml. of dichloromethane. The organic extract is washed once with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure to an oil. The oil is purified via column chromatography on 125 g. of silica gel eluted with 25% cyclohexane-ether to yield 172 mg. (15%) of 3-[4-(1,1-dimethylheptyl)-2-allyloxyphenyl]-1-N-(2-propenyl)-piperidine as an oil and 411 mg. (40%) of the title compound as an oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]2[CH2:59][CH2:58][CH2:57][C@H:43]2[C:44]([NH:46][CH:47]([CH:54]([CH3:56])[CH3:55])[C:48](=[O:53])[C:49]([F:52])([F:51])[F:50])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:29][CH:28]=1)(O)=[O:25].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:12]([O:19][C:20]([CH2:21][NH:22][C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]2[CH2:59][CH2:58][CH2:57][C@H:43]2[C:44]([NH:46][CH:47]([CH:54]([CH3:55])[CH3:56])[C:48](=[O:53])[C:49]([F:50])([F:51])[F:52])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:29][CH:28]=1)=[O:25])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)O)cc1)C(C)C)C(=O)C(F)(F)F
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)OCc2ccccc2)cc1)C(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a mixture of glycine benzyl ester p-toluene-sulfonate (66 mg) and 3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (100 mg) in DMF (6 ml) were added HOBT (26 mg) and WSCD (30 mg) under ice-bath cooling. After being stirred at room temperature for 4 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with 5% aqueous citric acid (20 ml), water (20 ml), 5% aqueous sodium bicarbonate (20 ml) and brine (20 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to give 3(RS)-[[4-[(benzyloxycarbonyl)methylaminocarbonyl]-phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (125 mg).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[N:51]([C:52]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:50]=[N:49][N:48]=2)=[CH:37][CH:36]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:14]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[N:51]([C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:50]=[N:49][N:48]=3)=[CH:39][CH:40]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(=O)c2cc(C=CC(=O)OCC)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc2ccc(C=CC(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
To a suspension of 1.75 g of ethyl 3-(2-butyl-1,4-dihydro-4-oxo-6-quinazolinyl)-2-propenoate in 25 ml of dry tetrahydrofuran at room temperature is rapidly added 6.70 g of a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. After stirring for 20 minutes at room temperature 3.899 g of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole is rapidly added in one portion and the reaction mixture heated at reflux for 48 hours. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and the organic layer washed with 5% HCl, water and brine. The organic layer is dried with MgSO4 and concentrated in vacuo to a residue which is purified by column chromatography on silicagel by eluting with 1:4 ethyl acetate-hexanes to give 1.732 g of the desired product as a solid. FAB MASS SPEC 799 (M+Na)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:30])=[CH:10][N:9]2[CH:21]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Solvent: ClCCl
Product: COC(=O)Nc1cn2cc(S(=O)c3ccccc3)ccc2n1

Procedure:
Alternatively, 0.59 g. (0.002 mole) of the product of Example 3 is combined with 0.406 g. (0.002 moles) of metachloroperbenzoic acid (85%) in 300 ml. of methylene chloride and stirred at room temperature overnight. The solution is washed with saturated aqueous sodium bicarbonate and evaporated to dryness affording 0.75 g. of crude product which is recrystallized from methylene chloride affording 2-(methoxycarbonylamino) 6-(phenylsulfinyl) imidazo [1,2-a] pyridine m.p. 247°-248° C.
Reaction SMILES: CCN(C1C=C[C:9]2[CH:12]=[C:13](/[CH:17]=[N:18]\[NH:19][C:20]3[N:25]=CC=CC=3)C([O:16][C:8]=2C=1)=O)CC.[S:26]([C:30]1[S:34][C:33]([C:35]2[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=2)[C:38]([OH:40])=O)=[CH:32][CH:31]=1)(=[O:29])(=[O:28])[NH2:27].FC1C=CC=CC=1C1[O:55]C(C(Cl)=O)=CC=1>>[O:16]1[CH:8]=[CH:9][CH:12]=[C:13]1[C:17]1[O:55][C:20]([NH:25][C:38]([C:37]2[CH:41]=[CH:42][CH:43]=[C:35]([C:33]3[S:34][C:30]([S:26](=[O:28])(=[O:29])[NH2:27])=[CH:31][CH:32]=3)[CH:36]=2)=[O:40])=[N:19][N:18]=1
Reactant: CCN(CC)c1ccc2cc(/C=N\Nc3ccccn3)c(=O)oc2c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2F)o1
Reactant: NS(=O)(=O)c1ccc(-c2cccc(C(=O)O)c2)s1
Product: NS(=O)(=O)c1ccc(-c2cccc(C(=O)Nc3nnc(-c4ccco4)o3)c2)s1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ic-2 described below, using an acid chloride which can be prepared from 3-(5-sulfamoyl-2-thienyl)benzoic acid described in Reference Example 2 by a routine method instead of 5-(2-fluorophenyl)-2-furancarbonyl chloride.
Reaction SMILES: [OH:1][C:2]1([NH:5][C:6]2([OH:9])[CH2:8][CH2:7]2)[CH2:4][CH2:3]1.[ClH:10].[Cl-].[OH:12]C1([NH2+]C2(O)CC2)CC1>>[Cl-:10].[OH:1][C:2]1([NH3+:5])[CH2:4][CH2:3]1.[C:6]([OH:9])(=[O:12])[CH2:8][CH3:7]
Reactant: OC1([NH2+]C2(O)CC2)CC1
Reactant: Cl
Reactant: OC1(NC2(O)CC2)CC1
Agent: [Cl-]
Product: CCC(=O)O
Product: [NH3+]C1(O)CC1

Procedure:
To bis(1-hydroxycyclopropyl)-amine (50 mg) [W. J. M. van Tilborg, Thesis, Amsterdam 1971] in D2O is added a small excess of conc. HCl. The NMR-spectrum shows a singlet for bis(1-hydroxycyclopropyl)-ammonium chloride (δD 2O = 1.25 (s, 4H)). The sample is heated at 80° for 4 hr yielding 1-hydroxycyclopropylammonium chloride (δD 2O = 1.17 (s, 4H)) and propionic acid. (The decomposition is much faster at higher HCl concentrations). Evaporation gives, as an oil, 1-hydroxycyclopropylammonium chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C(O)(C(F)(F)F)=O>>[F:13][C:14]([F:24])([F:25])[O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:22][CH:23]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 38.5 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-trifluoromethoxybenzaldehyde (2.4 g, 1 equiv.) and TFA (1.9 mL, 2 equiv.) to give the title compound (1.6 g, 38%) as a white powder. MP: 68-69° C.