Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)N[C:21](=[O:22])[CH:20]([CH2:127][C:128]2[CH:133]=[CH:132][C:131](O)=[CH:130][CH:129]=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)C.IC1C=CC=CC=1C(OC(C)(C)C)=O.Br[C:160]1[CH:165]=[CH:164][C:163]([F:166])=[CH:162][N:161]=1>>[F:166][C:163]1[CH:164]=[CH:165][C:160]([C:131]2[CH:130]=[CH:129][C:128]([CH2:127][CH2:20][CH:21]=[O:22])=[CH:133][CH:132]=2)=[N:161][CH:162]=1
Reactant: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Reactant: Fc1ccc(Br)nc1
Agent: CC(C)(C)OC(=O)c1ccccc1I
Product: O=CCCc1ccc(-c2ccc(F)cn2)cc1

Procedure:
The title compound was prepared following the procedure described for intermediate 1 substituting tert-butyl 2-iodobenzoate with 2-bromo-5-fluropyridine. 1H NMR (500 MHz, CDCl3) δ 9.83 (s, 1H), 8.52 (d, J=2.9 Hz, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.67-7.70 (m, 1H), 7.42-7.46 (m, 1H), 7.29 (d, J=8.2 Hz, 2H), 3.0 (t, J=7.6 Hz, 2H), 2.82 (t, J=7.3 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1>ClCCCC>[CH2:2]([N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C1CCNCC1
Solvent: CCCCCl
Product: CCCCN1CCC(=O)CC1

Procedure:
1-Butyl-4-piperidone is prepared from 4-piperidone and 1-chlorobutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][NH2:15]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][C:13]([F:17])([F:16])[F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(NCC(F)(F)F)c1ccc(Br)cc1
Yield: 26.2 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and 2,2,2-trifluoroethylamine (0.32 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(2,2,2-trifluoroethyl)benzenesulfonamide (0.13 g) was provided after purification. MS (ESI) m/z 318. HPLC purity 100.0% at 210-370 nm, 8.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][O:2][C:3](OC)=[N:4][NH:5][C:6]([O:8]C)=O.[CH3:12][NH2:13]>CO>[CH3:1][O:2][C:3]1[N:13]([CH3:12])[C:6](=[O:8])[NH:5][N:4]=1
Reactant: COC(=O)NN=C(OC)OC
Reactant: CN
Solvent: CO
Product: COc1n[nH]c(=O)n1C
Temperature: 70 °C

Procedure:
8.11 g (0.05 mol) of methyl N′-dimethoxymethylenehydrazinecarboxylate were dissolved in 25.4 g of methanol and admixed with 3.26 g (0.105 mol) of methylamine, dissolved in methanol, and the mixture was heated in an autoclave at 70° C. for 14 hours. The reaction mixture was concentrated under reduced pressure and taken up in water (10 ml). The mixture was acidified by addition of conc. HCl. The crystals which precipitated at 4° C. were filtered off and dried. This gave 1.89 g (29.3%) of 5-methoxy-4-methyl-2,4-dihydro-1,2,4-triazol-3-one in the form of a colourless solid. Melting point 146-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:19]O>S(Cl)(Cl)=O>[CH3:19][O:10][C:9](=[O:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:12][C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1
Reactant: CO
Reactant: O=C(O)C(=Cc1ccncc1)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=Cc1ccncc1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
The solution of 2-(4-Chloro-phenyl)-3-pyridin-4-yl-acrylic acid 3.5 g in thionyl chloride 25 mL was heated to 70° C. for five hours. The reaction was cooled to 0° C., then was added methanol 50 mL. After warm to room temperature over one hour, all the solvent removed under reduced pressure. Work up using ethyl acetate and sodium bicarbonate give the light yellow solid. MS (ES+): 274 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:8]2[N:9]=[CH:10][N:11]([CH3:24])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(ncn2C)c(Cl)c1Nc1ccc(Br)cc1Cl
Reaction time: 20 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 10dd (0.141 g, 0.34 mmol), potassium carbonate (0.141 g, 1.02 mmol), and iodomethane (0.063 mL, 1.02 mmol) are dissolved in dimethylformamide (3 mL). After 20 hours, the reaction mixture is diluted with EtOAc and washed with water (3×), potassium carbonate, and brine. The organic layer is dried (Na2SO4) and concentrated to a brown oil. The N3 and N1 alkylated regioisomers are separated by flash chromatography (EtOAc). The recovery of the N3 alkylated regioisomer is 20.4 mg (28%). MS ESI (+) m/z 428, 430 (M+, Br pattern) detected.
Reaction SMILES: [Cl:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CC1C=CC(S(OC)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[O:6][CH:7]([CH2:9][NH:10][C:27](=[O:28])[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cc(Cl)c3ccccc3c2O1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cc(Cl)c3ccccc3c2O1)OCc1ccccc1
Yield: 88.6 %

Procedure:
Treatment of (±)-1-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methanamine (0.83 g, 3.07 mmol) with diisopropylethylamine (1.20 g, 9.28 mmol) followed by benzyl chloroformate (0.79 g, 4.60 mmol) generally according to the procedure described for Intermediate 7 provided 1.00 g (89%) of (±)-benzyl (5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methylcarbamate as a white solid. mp 117-119° C.; Anal. calcd. for C21H18ClNO3.0.5H2O: C, 66.93; H, 5.08; N, 3.72. Found: C, 66.81; H, 4.96; N, 3.67.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Br:8][C:6]1[CH:7]=[C:2]([N:1]([S:27]([CH3:26])(=[O:29])=[O:28])[S:27]([CH3:26])(=[O:29])=[O:28])[C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[N:4][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of tert-butyl 3-amino-5-bromopyridin-2-ylcarbamate (96.3 mg, 0.33 mmol) and diisopropylethylamine (128 uL, 074 mmol) in dichloromethane (2 mL) was cooled to 0° C., and to it was added methanesulfonyl chloride (52 uL, 0.67 mmol). The mixture was allowed to warm to rt over 2 h. The mixture was then diluted with dichloromethane and was then washed with aqueous citric acid (10%) followed by water. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (gradient, 100% hexanes to 70% hexanes:30% ethyl acetate) to provide tert-butyl 5-bromo-3-(N-(methylsulfonyl)methylsulfonamido)pyridin-2-ylcarbamate (77 mg, 0.17 mmol, 52% yield) as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, 1H), 7.79 (d, 1H), 7.10 (s, 1H), 3.44 (s, 6H), 1.52 (s, 9H); MS (EI) for C12H18BrN3O6S2: 388, 390 (Br isotopes, MH+-t-butyl).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:28]=1)[C:18]1[CH:17]=[C:16]([O:19]C)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])=[CH:9][C:10]=1[F:21].C(Cl)Cl>>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:28]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])=[CH:9][C:10]=1[F:21]
Reactant: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(N3CCCC3=O)cc(F)c1O2
Solvent: ClCCl
Product: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1c(F)cc(N3CCCC3=O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-(2-amino-5′-fluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)pyrrolidin-2-one (377 mg, 0.98 mmol) in DCM (6 mL) boron tribromide (0.2 mL, 2.46 mmol) was added at 0° C. The bath was removed and the mixture was allowed to warm up to RT and stirred for 30 min. The reaction was quenched with sat NaHCO3 and diluted with DCM. The insoluble material was dissolved by adding MeOH. Organic layer was filtered through celite and concentrated to afford (S)-1-(2-amino-5′-fluoro-2′-hydroxy-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)pyrrolidin-2-one.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH:38]12[N:44]([C:45](=O)[CH2:46]Br)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>>[CH:38]12[N:44]([CH2:45][CH2:46][O:10][C:8]3[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=4[C@@H:12]4[CH2:21][CH2:20][C:19]5[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=5[CH2:13]4)=[CH:6][CH:7]=3)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CBr)N1C2CCC1CC2
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3C4CCC3CC4)cc2)c1
Yield: 152.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[CH:20][NH:21][C:14]=23)=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:23][CH2:24][O:25][CH3:26].BrOBr>O.CS(C)=O>[CH3:26][O:25][CH2:24][CH2:23][N:21]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][C:13]=2[S:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)[CH:19]=[CH:20]1
Reactant: O=[N+]([O-])c1ccc(Sc2ccnc3cc[nH]c23)cc1
Reactant: COCCBr
Agent: BrOBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COCCn1ccc2nccc(Sc3ccc([N+](=O)[O-])cc3)c21
Reaction time: 0.75 h

Procedure:
A sealed vial was charged with potassium hydroxide (0.124 g, 2.21 mmol) and DMSO (5 mL). 7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine (0.150 g, 0.553 mmol) was added and the reaction was stirred for 45 minutes. 1-Bromo-2-methoxyethane (0.104 ml, 1.11 mmol) was added, the system was flushed with argon, and the reaction was stirred at RT for 2 hours. LC-MS indicated starting material remaining, so 1 eq. bromoether was added and the reaction stirred for two more hours. The reaction was diluted with water and extracted four times with DCM and twice with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-5% MeOH:DCM) to afford 1-(2-methoxyethyl)-7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine as an orange oil that solidified under high vacuum. MS: M+H+=330.1
Reaction SMILES: [B-](F)(F)(F)F.CCN([S+](F)F)CC.[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)=O.[FH:32].[FH:33].F.C(N(CC)CC)C>ClCCl>[F:32][CH:14]([F:33])[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1
Reactant: F
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(C(F)F)CC1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a cooled (0° C.) solution of XtalFluor-E (4.50 g, 19.65 mmol) in dichloromethane (50 mL) was added a solution of 4-formyl-N-CBZ-piperidine (2.30 g, 9.30 mmol, Oakwood) in dichloromethane (7 mL) followed by triethylamine trihydrofluoride (3.00 mL, 18.40 mmol). The reaction was allowed to warm to room temperature overnight. Then the reaction mixture was cooled to 0° C. and quenched slowly with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco 40 g) eluting with (EtOAc):hexanes (0:1→1:1) to give benzyl 4-(difluoromethyl)piperidine-1-carboxylate as a light-yellow oil (1.16 g, 46% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: COc1ccc(C(=O)CBr)cc1
Product: CCOC(=O)n1c(C(=O)c2ccc(OC)cc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-4′-methoxyacetophenone.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[CH:29]([N:32]([CH2:36][CH2:37]Cl)[CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:37][CH2:36][N:32]([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)c1
Product: Cc1cccc(-c2nc3ccc(OCCN(C(C)C)C(C)C)cc3n2Cc2ccccc2C(F)(F)F)c1

Procedure:
The title compound was prepared essentially as described in Example 113 except that the compound of Example 120 was reacted with 2-(N,N-diisopropylamino)ethyl chloride. MS 510.
Reaction SMILES: [C:1]([CH2:9][CH:10]([OH:14])[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]([CH2:17][CH:18]([OH:23])[CH2:19][CH2:20][CH2:21][CH3:22])[NH2:16].N(CC(O)C)N.C(C(C)C(O)C(O)=O)(=O)C1C=CC=CC=1.C(NN)CCC.N(CC(O)CC)N>>[C:2]1([C:1]2[CH2:9][CH:10]([OH:14])[C:11](=[O:13])[N:15]([CH2:17][CH:18]([OH:23])[CH2:19][CH2:20][CH2:21][CH3:22])[N:16]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(O)C(=O)O)c1ccccc1
Reactant: CCCCC(O)CNN
Agent: CC(C(=O)c1ccccc1)C(O)C(=O)O
Agent: CC(O)CNN
Agent: CCC(O)CNN
Product: CCCCC(O)CN1N=C(c2ccccc2)CC(O)C1=O

Procedure:
When the above procedure is carried out using equivalent amounts of 3-benzoyl-2-hydroxy-propionic acid and 1-hydrazino-2-hexanol or 3-benzoyl-2-hydroxy-propionic acid and 1-hydrazino-2-propanol or 3-benzoyl-2-hydroxy-3-methyl-propionic acid and butyl hydrazine in place of the 3-benzoyl-2-hydroxy-propionic acid and 1-hydrazino-2-butanol used therein, there is obtained 6-phenyl-2-(2-hydroxyhexyl)-4-hydroxy-4,5-dihydropyridazine-3(2H)-one; 6-phenyl-2-(2-hydroxypropyl)-4-hydroxy-4,5-dihydropyridazin-3(2H)-one; or 2-butyl-4,5-dihydro-4-hydroxy-5-methyl-6-phenylpyridazin-3(2H)-one (m.p. 129°-155° C.), respectively.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3[CH:31]=[C:30]([C:32](=[O:44])[NH:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])[CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=3)[N:20]=2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3[CH:31]=[C:30]([CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=3)[C:32]([NH:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])=[O:44])[N:20]=2)=[CH:10][CH:9]=1
Reactant: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1cc(Nc2nccc(Oc3ccc(N)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Reaction time: 1 h

Procedure:
To a stirred solution of the product from step (v) above (540 mg, 0.825 mmol) in DCM (8 mL) was added TFA (3.2 mL, 41.5 mmol). The reaction was stirred at it for 1 h. The solution was concentrated in vacuo and the resulting oil dissolved in the minimum of MeOH and loaded onto SCX. The column was eluted with MeOH (3 column volumes), then 1% NH3 in MeOH (3 column volumes). The product-containing portion was concentrated in vacuo to afford the sub-title compound (405 mg) as a light, brown foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:21]=[CH:20][C:9]2[CH:10](O)[C:11]3[C:16]([CH2:17][S:18][C:8]=2[CH:7]=1)=[CH:15][CH:14]=[CH:13][N:12]=3.[OH-].[Na+]>C(Cl)Cl>[Cl:5][C:6]1[CH:21]=[CH:20][C:9]2[CH:10]([Cl:3])[C:11]3[C:16]([CH2:17][S:18][C:8]=2[CH:7]=1)=[CH:15][CH:14]=[CH:13][N:12]=3
Reactant: OC1c2ccc(Cl)cc2SCc2cccnc21
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1ccc2c(c1)SCc1cccnc1C2Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
Add thionyl chloride (3.1 mL, 0.0425 mol) dropwise to a stirred suspension of 8-chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-ol (8.8 g, 0.0334 mol) in CH2Cl2 (75 mL) at 3°-8° C. Stir the mixture at room temperature for 3 hours, and pour it into 150 mL of 2.5M NaOH containing ice. Filter, separate the aqueous layer and extract it with CH2Cl2 (2×50 mL). Combine the organic extracts, and wash with water (3×50 mL) and brine (1×75 mL). Dry the mixture over MgSO4, filter, and concentrate in vacuo to obtain the title compound (8.0 g, 80%).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]2[CH:12]([NH2:13])[CH:11]([CH2:14][CH2:15][O:16][CH3:17])[CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH:12]([NH:13][CH2:28][C:27]3[CH:30]=[C:31]([CH:34]([CH3:36])[CH3:35])[CH:32]=[CH:33][C:26]=3[O:25][CH3:24])[CH:11]([CH2:14][CH2:15][O:16][CH3:17])[CH2:10][NH:9]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(C(C)C)cc1C=O
Reactant: COCCC1CNC(C(c2ccccc2)c2ccccc2)C1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCCC1CNC(C(c2ccccc2)c2ccccc2)C1NCc1cc(C(C)C)ccc1OC
Reaction time: 18 h
Yield: 62 %

Procedure:
A solution of 109 mg (0.35 mmol) of [(2SR, 3SR, 4RS)-2-diphenylmethyl-3-amino-4-(2-methoxyethyl)pyrrolidine] (the product of Example 27B) in 35 ml of dichloroethane was treated with 63 mg (0.35 mmol) of 2-methoxy-5-isopropylbenzaldehyde and 104 mg (0.49 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred for 18 hours and then quenched with 30 ml of saturated aqueous sodium bicarbonate. The reaction mixture was extracted with methylene chloride and the organic phase was washed with brine, dried and evaporated. The residue was chromatographed on silica gel eluting with 97/2/1 (methylene chloride/methanol/ammonia) to afford 102 mg (62%) of the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5])#[N:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[C:1]([C:3](=[CH:13][N:14]([CH3:16])[CH3:15])[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)c1ccsc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)c1ccsc1

Procedure:
2-Cyano-3-dimethylamino-1-thien-3-ylpropen-1-one was prepared from 3-cyanoacetyl thiophene (7.64 g,50.56 mmol) and dimethylformamide dimethylacetal (20 mL, 152 mmol) as a yellow solid (6.6 g), m.p. 134°. δH (CDCl3) 8.27 (1H, dd, J 3.0, 1.3 Hz), 8.00 (1H, s), 7.61 (1H, dd, J 5.0 Hz), 7.27 (1H, dd, J 5.0,3.0 Hz), 3.48 (3H, s) and 3.29 (3H, s).
Reaction SMILES: C(N(CC)CC)C.Cl.CN(CCO[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](Cl)[CH:22]=2)[N:17](C2C=CC(F)=CC=2)[C:16]=1[CH2:32]O)C.CS([Cl:38])(=O)=O.O>ClCCl>[Cl:38][CH2:32][C:16]1[NH:17][C:18]2[C:23]([CH:15]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCOc1c(CO)n(-c2ccc(F)cc2)c2ccc(Cl)cc12
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cc2ccccc2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (1 g) was added to a solution of N,N-dimethyl-2-[5-chloro-1-(4-fluorophenyl)-2-hydroxymethyl-3-1H-indolyloxy]ethylamine 9 (3 g) in dichloromethane (100 mL) cooled to -10° C. A solution of methanesulfonylchloride (1.1 g) in dichloromethane (25 mL) was added dropwise at -10° to 0° C. After stirring for 1/2 h at 0° C. ice cooled water was added and the organic phase was subsequently worked up leaving the 2-chloromethylindole derivative as an oil. This oil was used immediately without further purification. To a solution of the oil in dry THF was added LiAlH4 (1 g). After refluxing for 1 h, the mixture was cooled on an ice bath and excess LiAlH4 was hydrolyzed by cautiously adding a mixture of 10% water in THF. Inorganic salts were filtered off and the solvent evaporated in vacuo . The resulting visceous oil was subjected to column chromatography on silica gel (eluted with 4% triethylamine in ethyl acetate) yielding the pure title compound as an oil. Yield: 0.6 g. The oxalic acid salt 10 crystallized from 2-propanol. mp 236°-237° C.; 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.85 (s, 6H), 3.40 (t, 2H), 4.35 (t, 2H), 7.00 (d, 1H), 7.05 (dd, 1H), 7.40 (t, 2H), 7.45 (dd, 2H), 7.70 (d, 1H). MS (m/z) 347 (MH+), 274 (6), 223 (36), 222 (20), 72 (100); Anal (C19H20ClFN2O.C2H2O4) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.C(=O)([O-])O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CC(C)=O.C(OCC)C>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])[S:3][CH:4]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1)OCC(Cl)(Cl)Cl
Yield: 68.5 %

Procedure:
Into 300 ml of acetone, were added 2.2 g of 2-amino-4-p-nitrophenylthiazole and 3.0 g of sodium hydrogen carbonate. To the resulting mixture, 6.3 g of 2,2,2-trichloroethyl chloroformate in 20 ml of acetone was added dropwise, followed by a stirring for 10 hours at the reflux temperature. Inorganic substances were filtered off and the filtrate was concentrated. Any substances, which were insoluble in diethyl ether, were removed from the concentrate. A crude reaction product resulting from the remaining portion, which was soluble in diethyl ether, was subjected to silica gel column chromatography. It was then eluted with a mixed solvent of chloroform-acetone (10:1) and thereafter recrystallized from chloroform to obtain 2.7 g of 2,2,2-trichloroethyl N-(4-p-nitrophenyl-2-thiazolyl)carbamate.