Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1cccnc1
Product: O=C(NCc1cccnc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 3-picolylamine (35 mg, 0.32 mmol). The title compound was obtained as a yellow solid (21 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.42 (1H, m), 8.99 (2H, s), 8.51 (1H, s), 8.47 (1H, s), 7.69 (1H, m), 7.36 (1H, m), 4.43 (2H, m). MS m/z: 441.17, 443.16 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>ClCCl>[CH3:21][S:22]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4S(C)(=O)=O)c2n1

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (2.53 g, 9.64 mmol) (Intermediate 10.1), methanesulfonyl chloride (1.12 ml, 14.47 mmol), and triethylamine (2.94 ml, 21.22 mmol) in dichloromethane (50 ml) is stirred for 30 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 3.24 g (99%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 7.16 min (tR(SM) 6.64 min). MS (ESI) m/z (C17H16N4O2S) 341.1 (M+1, 100) Finnegan LCQ.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(C#N)=NO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=NOS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
In ethyl acetate (50 ml) are dissolved ethyl 2-hydroxyimino-2-cyanoacetate (7.1 g) and triethylamine (7.0 ml). To the solution is added p-toluenesulfonyl chloride (9.5 g) with stirring under ice-cooling, and the mixture is stirred for 2 hours and allowed to stand overnight. The reaction mixture is filtered and the filtrate is concentrated. To the residue is added cyclohexane and the resulting crystals are separated by filtration and dried to give ethyl 2-(p-toluenesulfonyloxyimino)-2-cyanoacetate (13.9 g), melting point: 84°-87° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[O:4]1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:9][C:7]1([CH3:8])[C:3]([CH3:16])([CH3:2])[O:4][B:5]([C:10]2[CH2:11][CH2:12][N:13]([CH2:19][CH2:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH:15]=2)[O:6]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)CCN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (100 mg), tert-butyl acrylate (0.089 mL), potassium carbonate (169 mg), and acetonitrile (2 mL) was stirred overnight at 70 C. In another reaction vessel, a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (1.00 g), tert-butyl acrylate (0.895 mL), potassium carbonate (1.688 g), and acetonitrile (10 mL) was stirred overnight at 70 C. These two reaction mixtures were combined, and water was added thereto, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to obtain the title compound (1.11 g).
Reaction SMILES: C[O:2][C:3](=[O:42])[C@@H:4]([NH:8][C:9](=[O:41])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[N:26]=[C:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:28][C:29]=3[C:30]([F:33])([F:32])[F:31])=[O:24])=[CH:18][N:17]=2)=[C:12]([Cl:40])[CH:11]=1)[CH:5]([CH3:7])[CH3:6].CO.O.O.[OH-].[Li+]>O1CCCC1>[Cl:40][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[N:26]=[C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:28][C:29]=2[C:30]([F:31])([F:33])[F:32])=[O:24])=[CH:18][N:17]=1)[C:9]([NH:8][CH:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:42])=[O:2])=[O:41]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(NC(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1)C(=O)O
Yield: 92 %

Procedure:
A solution of (S)-2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid methyl ester (30 mg, 0.05 mmol) in a mixture of tetrahydrofuran, methanol and water (3:1:1, 2 mL) was treated with lithium hydroxide monohydrate (6 mg, 0.15 mmol) at 50° C. for an hour. The reaction mixture was concentrated, diluted with water and the pH was adjusted to 1-2 with dilute hydrochloric acid (1N). The white precipitate was collected by centrifugation, and then was dried under vacuum to give 2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid (27 mg, 93%) as a white solid. LCMS calcd for C28H22ClF3N4O5 (m/e) 586, obsd 587 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH3:13])[N:9]=[CH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:13][C:8]1[N:9]=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=2
Reactant: COc1ccc2cc(C)ncc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2ccc(O)cc2cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.5 %

Procedure:
7-Methoxy-3-methylisoquinoline (15 g, 89 mmol, 1 equiv.) was dissolved in methylene chloride (150 mL). A 1.0 M solution of BBr3 in methylene chloride (240 mL, 240 mmol, 2.7 equiv.) was added slowly to this solution at room temperature observing a slight exotherm. This solution was stirred at room temperature for 2.5 hours. After cooling to 0° C., methanol (150 mL) was added slowly to quench the reaction. The solution was stirred for an additional 15 minutes. The solution was concentrated under reduced pressure and treated with methanol (150 mL) and concentrated under reduced pressure. The resulting oil was treated with saturated aqueous sodium bicarbonate slowly with stirring until a pH˜7-8 was achieved. The solid resulting was collected under vacuum filtration and was washed with water (300 mL) and methylene chloride (200 mL) giving a tan solid which was dried in a vacuum oven at 50° C. overnight to give 3-methylisoquinolin-7-ol (13.1 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14]C)=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[BrH:16]>>[BrH:16].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1CCNCC1
Agent: Br
Product: Oc1ccc(Cl)cc1C1CCNCC1
Yield: 97 %

Procedure:
To 4-(5-chloro-2-methoxyphenyl)piperidine (Preparation 233, 40 g, 0.177 mol) was added hydrogen bromide (48% in water, 100 ml) and refluxed for 24 hours before concentrating in vacuo. 1,4-Dioxane was added and solution concentrated in vacuo. The resulting crystals were washed with diethyl ether and dried in vacuo to give the title compound as white crystals, 53 g, 97% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:38])([F:39])[F:23])=[CH:30][CH:29]=4)=[CH:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 44.8 %

Procedure:
The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (153 mg, 0.418 mmol) and 4-(4-(trifluoromethy)phenyl)pyridine-2(1H)-one (100 mg g, 0.418 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (98 mg, 45%) as a yellow/green solid: 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 4H), 7.57-7.53 (m, 2H), 7.37 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.50 (d, J=6.7 Hz, 1H), 4.67 (s, 2H), 3.86 (br s, 2H), 3.60 (s, 3H), 2.84 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[C:5](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:18])[C:4]=2[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:41]1[C:49]2[N:48]=N[NH:46][C:45]=2[CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[C:5](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:46][C:45]3[CH:44]=[CH:43][CH:42]=[CH:41][C:49]=3[NH2:48])=[O:26])=[O:18])[C:4]=2[CH:3]=1
Reactant: O=C(O)CCCCCNC(=O)C=C1c2cc(Cl)ccc2-c2ccc(Cl)cc21
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)CCCCCNC(=O)C=C1c2cc(Cl)ccc2-c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
6-(2-(2,7-dichloro-9H-fluoren-9-ylidene)acetamido)hexanoic acid (403 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (351 mg, 71% yield) as a brown solid. LC-MS (m/z) 494 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Product: CC1=C2C[C@@]3(C)C(=CC[C@H](OC(=O)c4ccccc4)[C@@H]3C)C=C2OC1=O

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with benzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=CC=2N=[N:31]1.C(N(CC)C(C)C)(C)C.Cl.NN1CCCC1.[Cl-].[Na+]>CN(C=O)C>[N:30]1([NH:31][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Agent: NN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCCC2)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (200 mg, 0.6 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (291 mg, 0.91 mmol), N,N-diisopropyl ethyl amine (510 μL, 3.0 mmol) and N-aminopyrrolidine HCl (111 mg, 0.91 mmol). The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water, citric acid solution and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane) afforded the title compound (139 mg, 58%) as a colorless oil. MS: m/e=400.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([OH:16])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]3)[C:21]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([NH:31][C@H:28]3[CH2:29][CH2:30][N:26]([C:22]4[C:21]5[N:20]([CH:19]=[CH:18][N:17]=5)[CH:25]=[CH:24][N:23]=4)[CH2:27]3)=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Reactant: O=C(O)c1ncn(-c2ccc(F)c(F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1ncn(-c2ccc(F)c(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of 1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (0.10 g, 0.44 mmol, 1 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.12 g, 0.44 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.19 mL, 0.49 mmol, 1.1 eq) and HATU (0.19 g, 1.3 mmol, 3 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)-1-(3,4-difluorophenyl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide (0.046 g, 0.11 mmol, 25%).
Reaction SMILES: C([Li])CCC.[OH:6][C:7]([C@@H:10]1[C@@H:13]([CH2:14][CH:15]=[CH2:16])[N:12]([C:17](=[C:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:11]1=[O:25])([CH3:9])[CH3:8].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(O)(=O)C>O1CCCC1>[CH3:23][C:22]([CH3:24])=[C:17]([N:12]1[C@H:13]([CH2:14][CH:15]=[CH2:16])[C@@H:10]([C:7]([CH3:9])([O:6][C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:28])[CH3:8])[C:11]1=[O:25])[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CC[C@@H]1[C@@H](C(C)(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
A solution of n-butyl lithium (0.42 ml of 1.55M solution in hexane) was added to a solution of methyl 2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (150 mg) in tetrahydrofuran (3 ml) during 3 minutes at -70° C. and the mixture was stirred for 5 minutes at -70° C. A solution of p-nitrobenzyl chloroformate (161 mg) in tetrahydrofuran (1.6 ml) was added to the mixture during 5 minutes at -70° C. and the mixture was stirred for 15 minutes at -70° C. The mixture was allowed to warm to 0° C. during 30 minutes and stirred for 2 hours at 0° C. Acetic acid (0.037 ml) was added to the mixture at 0° C. and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate ( 50 ml), and the sodium was washed with water (10 ml), 10% phosphoric acid (10 ml), phosphate buffer (pH 7.0) (10 ml×2), aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of hexane and ethyl acetate (5:1-1:1) to give methyl 3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate (135 mg) as an oil.
Reaction SMILES: O.[ClH:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[NH:17])=[CH:8][CH:7]=1)([O-])=O>CO>[ClH:2].[NH2:3][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[NH:17])=[CH:8][CH:7]=1
Reactant: N=C1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: N=C1CCCN1c1ccc(N)cc1
Reaction time: 17 h

Procedure:
2.5 g of water-moist palladium on activated carbon (5% of Pd) are added to a solution of 25.0 g (103 mmol) of 1-(4-nitrophenyl)pyrrolidin-2-ylideneamine, hydrochloride, in 500 ml of methanol, and the mixture is hydrogenated at room temperature for 17 hours. The catalyst is filtered off, and the filtrate is evaporated, giving 1-(4-aminophenyl)pyrrolidin-2-ylideneamine, hydrochloride, as a brownish solid; ESI 176.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH3:5][C:3]1[CH2:2][C:1](=[O:7])[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Product: CC1=NN(c2ccccc2)C(=O)C1
Reaction time: 3 h
Yield: 65 %

Procedure:
Into 50 ml of ethanol, 13.0 g of ethyl acetoacetate and 10.8 g of phenylhydrazine were added, and the mixture was refluxed under stirring for 3 hours. After left to cool, the precipitated crystals were filtered and recrystallized from ethanol to obtain 11.3 g of 3-methyl-1-phenyl-2-pyrazolin-5-one (Compound No. 1) as colorless crystals.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][CH2:12][C:11](=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=O)[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].N1(CC=C2CCCC3N(C4C=CC=CC=4)N=CC2=3)CCOCC1>C1COCC1>[N:19]1([CH2:17]/[CH:16]=[C:11]2/[C:10]3[CH:9]=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:15]=3[CH2:14][CH2:13][CH2:12]/2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C(C=C1CCCc2c1cnn2-c1ccccc1)N1CCOCC1
Agent: C(CN1CCOCC1)=C1CCCc2c1cnn2-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C(\CN1CCOCC1)=C1\CCCc2c1cnn2-c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 30.9 %

Procedure:
An E/Z mixture of 4-(2-(1-phenyl-6,7-dihydro-1H-indazol-4(5H)-ylidene)acetyl)-morpholine (398 mg, 1.23 mmol) is added to a mixture of LiAlH4 (129 mg, 3.70 mmol) in THF (10 mL) cooled to 0° C. The temperature of the reaction is allowed to increase up to room temperature and is stirred for 4 hours, and then the reaction is refluxed for 30 minutes. The mixture is cooled in an ice bath and ice is added. The insoluble solid is filtered and washed with AcOEt. The organic phase is washed with H2O, dried and evaporated under reduced pressure, giving an E/Z mixture of 4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethylidene)-1-phenyl-1H-indazol which is purified by means of silica gel chromatography giving (E)-4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethylidene)-1-phenyl-1H-indazole (118 mg, 0.38 mmol, 31%) and an E/Z mixture of 4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethylidene)-1-phenyl-1H-indazole (80.2 mg, 0.26 mmol, 21%).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Cl:17])=[N:7][N:8]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:19].N([O-])=O.[Na+]>O>[Cl:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([OH:19])=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=1
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)Cn1nc(Cl)c2ccc(N)cc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cn1nc(Cl)c2ccc(O)cc21
Temperature: -5 °C

Procedure:
Ethyl 6-amino-3-chloroindazol-1-ylacetate (11.5 g) was warmed with 35% sulphuric acid to obtain a solution. Ice (54 g) was added and the solution cooled to -5° C. in an ice/salt bath. A solution of sodium nitrite (4 g) in water (43cm3) was added slowly with stirring and cooling at 0° C. When addition was complete, the mixture was stirred for 15 minutes at 0° C. A pre-cooled solution (5° C.) of cupric nitrate (173 g) in water (1.6L) was added with stirring and cooling at 5° C. Cooper (I) oxide (6.5 g) was added and the mixture stirred at 0° C. for 0.5 hours, after which it was allowed to warm to room temperature for 4.5 hours. The reaction mixture was extracted with ethyl acetate (×4) and the combined organic phase washed with water, dried (MgSO4), filtered and the solvent removed from the filtrate under vacuum. The residue was stirred with ethanol (400cm3) saturated with hydrogen chloride overnight, evaporated under vacuum and then partitioned between water and ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and the solvent removed from the filtrate under vacuum. The residue was purified by flash chromatography (SiO2 ; chloroform:ether,3:2) to give ethyl 3-chloro-6-hydroxyindazol-1-ylacetate (4.34 g) as a brown solid; recrystallised from toluene, m.pt 138°-142° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)C2CCCCC2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccc(Br)cc1)C1CCCCC1)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-3-cyclohexyl-1-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless solid, MS (ESI+): m/z=388.2 [M+H]+.