Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:3]([N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:33]([NH:40][C:41](=[O:51])[NH:42][C@H:43]([CH2:48][CH:49]=[CH2:50])[CH2:44][C:45](O)=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:14]([N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:45](=[O:46])[CH2:44][CH:43]([NH:42][C:41]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:51])[CH2:48][CH:49]=[CH2:50])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:26][CH:27]=1)=[O:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1ccccc1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2 (50 ml) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCI (1.17 g, 7.3 mmol, 1.2 eq), HOBt (0.93 g, 7.3 mmol, 1.2 eq), DIEA (2.13 mL, 12.2 mmol, 2.4 eq) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 687 (M+H), 709 (M+Na)
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[OH:17])[N:6]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:5]1[N:6]=[C:2]([NH2:1])[O:3][CH:4]=1
Reactant: Nc1nc(-c2c(O)ccc3ccccc23)co1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ccccc2c1-c1coc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(2-Amino-oxazol-4-yl)-naphthalen-2-ol (22, 190 mg) was dissolved in N,N-dimethylformamide and then sodium hydride (34 mg) was added in one portion to give a dark orange solution. Methyl bromoacetate (88 μL) was then added and the mixture was stirred at room temperature for 18 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21]Cl)=[CH:9][N:8]=1.[C-:26]#[N:27].[Na+].[I-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21][C:26]#[N:27])=[CH:9][N:8]=1
Reactant: COc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2ncc(CC#N)c3cc(OC)c(OC)cc23)c1
Yield: 47.4 %

Procedure:
The above 1-(3-methoxybenzyl)-4-chloromethyl-6,7-dimethoxyisoquinoline (361 mg, 1.0 mmol) was suspended into 15 ml of 90% ethanol. Then sodium cyanide (392 mg, 8.0 mmol) and sodium iodide (83 mg, 0.5 mmol) was added. The mixture was refluxed for 4 hrs. solvents were evaporated and the residue was extracted with ethyl acetate. After the evaporation of solvents, the residue was purified by flash column chromatography using ethyl acetate and hexane (2/1) to give 1-(3-methoxybenzyl)-4-cyanomethyl-6,7-dimethoxyisoquinoline as a solid (165 mg, 47.4%). ES-MS calculated for C21H20O3N2 (m/e) 348.41, observed 349.5.5 (M+1). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]#[N:15])[CH:10]=[CH:11][CH:12]=2)[N:5]=[N:4][N:3]=1>C1COCC1>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][CH:12]=2)[N:5]=[N:4][N:3]=1
Reactant: Cc1nnnn1-c1cccc(CC#N)c1
Solvent: C1CCOC1
Product: Cc1nnnn1-c1cccc(CCN)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a solution of 3-(5-methyl-tetrazol-1-yl)-phenyl-acetonitrile (180 mg, 0.90 mmol) in THF (3 mL) was added a solution of borane-methyl sulfide complex in THF (2M, 0.8 mL, 1.60 mmol) slowly at 0° C. and the resulting mixture was refluxed at 80° C. under nitrogen for 2 h. The reaction was quenched with MeOH and stirred at room temperature for 1 h. The mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (10-26% ethyl acetate in petroleum ether) to afford the title compound (85 mg, 0.42 mmol, 46% yield). MS (ESI) m/z 204.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH3:20][O:21]C1C=CC=C2C=1C=CN2>>[CH3:20][O:21][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH:7]=[C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[NH:9]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: COc1cccc2[nH]ccc12
Product: COc1cccc2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 4-methoxy-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34]C)=[C:6]([C:8]([CH3:33])([CH3:32])[CH2:9][C:10]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:25])[F:24])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:34])=[C:6]([C:8]([CH3:32])([CH3:33])[CH2:9][C:10]([C:28]([F:29])([F:30])[F:31])([OH:27])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:24])[F:25])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C(F)(F)F)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CC(O)(CNc1cccc2nc(C(F)(F)F)ccc12)C(F)(F)F)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100 mg (0.20 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)quinolin-5-ylamino)pentan-2-ol in 2.0 ml of dichloromethane is mixed at room temperature with 4.0 ml (4.0 mmol) of a 1 M boron tribromide solution. After 20 hours at room temperature, the reaction is brought to a halt by adding 20 ml of methanol. The reaction mixture is allowed to stir for 30 minutes at room temperature, and then the solvent is removed in a vacuum. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 79 mg (80% of theory) of the product is obtained.
Reaction SMILES: N[C@H](C(O)=O)C(C)(C)C.[BH4-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:26](=[O:27])[C:25](=[O:28])[NH:24][C:23]3[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=3[S:21]2)=[CH:16][CH:15]=1.Cl>C(OCC)(=O)C.O1CCCC1>[OH:27][C@H:26]1[C:25](=[O:28])[NH:24][C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[S:21][C@H:20]1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(C2Sc3ccccc3NC(=O)C2=O)cc1
Agent: CC(C)(C)[C@H](N)C(=O)O
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: -15 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
A mixture of L-tert-leucine (393 mg), sodium borohydride (98 mg) and tetrahydrofuran (100 ml) is refluxed under nitrogen atmosphere for three hours. The mixture is cooled to -15° C., and thereto is added 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (599 mg), and the mixture is further stirred at -15° C. for 48 hours. To the reaction solution are added 1N hydrochloric acid (10 ml) and ethyl acetate (20 ml), and the mixture is stirred for 30 minutes. The organic layer is separated, washed with water, dried, and evaporated under reduced pressure to remove the solvent. The resulting residue is dissolved in ethanol (22 ml) with heating, and the mixture is cooled gradually for crystallization. The precipitated crystal is collected by filtration to give (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (376 mg).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccccc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#Cc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In particular 2-cyano-benzothiazole 10 (0.84 mmol, 0.134 g) was suspended in 0.563 ml conc. H2SO4 at 0° C. 1.3 equivalents of concentrated HNO3 (1.1 mmol, 0.069 g) was added portionwise over 10 min to the stirring solution; not to exceed 0° C. over a total of ˜45 min. The reaction proceeded further for 2 h and at 5 h the product was evident. The reaction was then poured over ice/water, extracted into EtOAc, and concentrated in vacuo to yield a crude yellow residue 11. For analytical characterization, a small portion was purified by semi-preparative HPLC at 10 mL/min on a Waters preparative machine (Waters Symmetry prep C18, 7 μm, 19×300 mm column, photodiode array detection) with a linear gradient from 90% H2O (0.1% TFA) to 50% MeCN (0.1% TFA) for 30 min yielding a large product peak at ˜27 minutes. The fractions were collected and lyophilized using Kinetics Flexi-Dry freeze-dryer.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[N:7]=[CH:6][C:5]=1[C:19](O)=[O:20])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:58]([O:62][C:63]([NH:65][C:66]([NH2:68])=[NH:67])=[O:64])([CH3:61])([CH3:60])[CH3:59]>CN(C)C=O>[C:58]([O:62][C:63]([NH:65][C:66]([NH:68][C:19]([C:5]1[CH:6]=[N:7][N:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[C:4]=1[CH:1]([CH3:2])[CH3:3])=[O:20])=[NH:67])=[O:64])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: CC(C)c1c(C(=O)O)cnn1-c1ccc2ncccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1c(C(=O)NC(=N)NC(=O)OC(C)(C)C)cnn1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.5 %

Procedure:
To a solution of 5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid (336.7 mg, 1.2 mmol) in 5 ml dimethylformamide was added N,N-diisopropylethylamine (0.42 ml, 2.39 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) (582 mg, 1.32 mmol) and tert-butoxycarbonylguanidine (210 mg, 1.32 mmol). The resulting solution was stirred at room temperature for 2 h, then heated to 60° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated to dryness in vacuo. The solid residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (sodium sulfate) and concentrated to dryness in vacuo. The solid residue was triturated with methanol (1.5 ml), filtered, washed with diethyl ether and dried to yield the title compound as a white solid (114.3 mg, 22.5% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[C@H:3]1[C:15]([O:17]C(C)(C)C)=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:22][C:2]1([CH3:1])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16]
Reactant: CCCCCOC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)C#C[C@H]1[C@@H](C(=O)O)C1(C)C
Yield: 112 %

Procedure:
A mixture of 5.24 g of the product of Step A, 50 ml of toluene and 250 mg of p-toluene sulfonic acid was refluxed until gas evolution ceased and was then evaporated to dryness under reduced pressure to obtain 4.8 g of crude (1R,cis)2,2-dimethyl-3-(pentyloxycarbonyl-ethynyl)-cyclopropane-carboxylic acid which was used as is for the next step.
Reaction SMILES: [CH2:1]([Cl:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C(Cl)/C=C(\CCC=C(C)C)/C.CC(C)=CCCC(C=C)=C>>[CH3:9][C:8]([CH3:10])=[CH:7][CH2:6][CH2:5][C:3]([CH:2]=[CH2:1])=[CH2:4].[ClH:11]
Reactant: CC(C)=CCC/C(C)=C/CCl
Agent: C=CC(=C)CCC=C(C)C
Agent: CC(C)=CCC/C(C)=C\CCl
Product: Cl

Procedure:
The mixture of geranyl chloride and neryl chloride can be obtained by hydrochlorination of myrcene in the presence of one mole of anhydrous hydrogen chloride per mole of myrcene under the conditions described above for the preparation of 1,7-dichloro-3,7-dimethyl-octene.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[C:37]12([N:47]=[C:48]=[O:49])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2.C(N(CC)CC)C>CN(C)C=O>[C:37]12([NH:47][C:48]([NH:3][C:4]3[CH:36]=[CH:35][CH:34]=[C:6]([O:7][C:8]4[CH:9]=[CH:10][C:11]5[N:15]=[C:14]([CH2:16][O:17][C:18]6[CH:31]=[CH:30][C:21]([CH2:22][CH:23]7[S:27][C:26](=[O:28])[NH:25][C:24]7=[O:29])=[CH:20][CH:19]=6)[N:13]([CH3:32])[C:12]=5[CH:33]=4)[CH:5]=3)=[O:49])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(NC(=O)NC45CC6CC(CC(C6)C4)C5)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.9 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), 1-adamantyl isocyanate (142 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (4 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1→4:1→ethyl acetate as the eluant. The product insoluble in methanol was isolated by filtration and further purified by preparative reverse phase high performance liquid chromatography using acetonitrile:water=50:50→60:40→65:35→70:30 as the eluant to afford the title compound (66 mg, mp 227.1-231.4° C.).
Reaction SMILES: [N:1](=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]1=[O:15])O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>[Pd]>[C:16]([NH:1][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]1=[O:15])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)C(=O)C(=NO)CC2
Agent: [Pd]
Product: COc1ccc2c(c1)C(=O)C(NC(C)=O)CC2
Reaction time: 3 h

Procedure:
A mixture of 2-oximino-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (8.7 gm, 0.04 m), palladium on carbon (10%, 1 gm) tetrahydrofuran (150 ml) and acetic anhydride (25 ml) was hydrogenated on a Parr apparatus for 3 hours. The catalyst was filtered, and the solvents were removed under reduced pressure to yield the product as an oil, which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[Li+].[Br-:13]>>[Br:13][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: [Br-]
Reactant: Cn1ncc([N+](=O)[O-])c1CCl
Agent: [Li+]
Product: Cn1ncc([N+](=O)[O-])c1CBr
Yield: 70 %

Procedure:
Reaction of 5-(chloromethyl)-1-methyl-4-nitro-1H-pyrazole (80 mg, 0.54 mmol) with LiBr according to general procedure B gave 5-(bromomethyl)-1-methyl-4-nitro-1H-pyrazole (70 mg, 70%) as a white crystalline solid, m.p. 71-73° C. 1H NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 4.82 (s, 2H), 3.95 (s, 3H). Analysis found: C, 27.76; H, 3.08; N, 18.99. C5H6BrN3O2.0.02hexane requires: C, 27.73; H, 2.86; N, 18.95. HRMS (FAB+) found: 219.97223, 221.97012 (M+1), calcd. for C5H279/81BrN3O2: 219.97216, 221.97012.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:16][C:15]=3[NH:14][C:13]([CH3:25])=[C:12]2[C:26]#[N:27])=[CH:4][C:3]=1[Br:28].C(O)(=O)C>C1COCC1.[Zn]>[NH2:8][C:7]1[CH:6]=[C:5]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:16][C:15]=3[NH:14][C:13]([CH3:25])=[C:12]2[C:26]#[N:27])[CH:4]=[C:3]([Br:28])[C:2]=1[NH2:1]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(N)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(N)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-(4-Amino-3-bromo-5-nitro-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (600 mg) was dissolved in THF (150 ml) and cooled to 0° C. Acetic acid (1.3 ml) was added, followed by addition of zinc dust (2 g). The resulting slurry was stirred at 0° C. for 2 h, and then another 4 h at room temperature. The mixture was filtered and diluted with saturated aq. NaHCO3, followed by extraction with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 3/1→0/1 (v/v) as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C3=NCCO3)cc2)CC1

Procedure:
2.4 g (7 mmool) of 1-tert.butoxycarbonyl-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine, dissolved in 70 ml of anhydrous ethanol and 20 ml of ethyl acetate, are catalytically hydrogenated (ambient temperature, 20 minutes, hydrogen pressure 50 psi) in the presence of 2.5 g of palladium-carbon (10%). The catalyst is suction-filtered, the filtrate is evaporated down and the residue is reacted further without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH:15]C(OCC3C=CC=CC=3)=O)=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26])=[O:4].[H][H]>CO.C1COCC1.[C].[Pd]>[CH3:1][N:2]([CH3:27])[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH2:15])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26])=[O:4]
Reactant: [H][H]
Reactant: CN(C)C(=O)C1Cc2ccc(NC(=O)OCc3ccccc3)cc2NC1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)C1Cc2ccc(N)cc2NC1=O
Yield: 92.2 %

Procedure:
To a suspension of N,N-dimethyl-7-benzyloxycarbonylamino-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (820 mg) in methanol (8 ml) and THF (8 ml) was added 10% palladium-carbon (100 mg). The reaction mixture was stirred under one atmospheric pressure of hydrogen at room temperature for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The precipitated crystals were washed with combined solution of IPE and THF to obtain the entitled compound (480 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1.[CH:16](I)([CH3:18])[CH3:17]>CN(C=O)C>[CH:16]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:15])([CH3:3])[CH2:5][C:6]1=[O:14])([CH3:18])[CH3:17]
Reactant: CC(C)I
Reactant: CC1(C)CC(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CC(C)(C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of NaH (0.121 g, 3.0 mmol) in dry DMF (2 mL) was added a solution of 4,4,-dimethyl-2-oxoquinoline (Compound 38, 0.529 g, 3.0 mmol) in dry DMF (10 mL). The mixture was stirred at room temperature for 30 min followed by addition of isopropyl iodide. The reaction mixture was left at room temperature for 72 h. Then ice-cubes were added to the reaction and the mixture was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with saturated solution of NaCl, dried over MgSO4 and concentrated to give a pale yellow oil. Purification by column chromatography (silica gel, 30% ethyl acetate in hexane) yielded the title compound as a colorless oil (472 mg, 72%). 1H NMR d 1.32 (s, 6H), 1.57 (d, J=7.1 Hz, 6H), 2.45 (s, 2H), 4.74 (q, J=7.0 Hz, 1H), 7.06-7.32 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=O)[N:13]=2)=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[NH2:58][CH2:59][C:60](=[O:62])[CH3:61]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:58][CH2:59][C:60](=[O:62])[CH3:61])=[O:18])[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(=O)CN
Reactant: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.800 g, 1.90 mmol), HOBT-H2O (0.437 g, 2.86 mmol), DIEA (1.36 mL, 7.80 mmol), EDCI (0.547 g, 2.86 mmol), and 1-aminopropan-2-one hydrochloride (0.834 g, 7.61 mmol) in 50 mL THF was stirred at 50° C. for 2 days. The mixture was concentrated and diluted with CH2Cl2 and washed with water, dried over sodium sulfate and concentrated to a residue that was carried on to the next step without further purification.