Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCCN(C(=O)OC(C)(C)C)CC1
Yield: 68.4 %

Procedure:
To a microwave reaction vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (500 mg, 3.10 mmol), tert-butyl 1,4-diazepane-1-carboxylate (744 mg, 3.72 mmol). Ethanol (15 mL) and diisopropylethylamine (3.23 mL, 18.57 mmol) were added and the mixture was irradiated with a microwave for 60 min at 130° C. The mixture was cooled, concentrated and purified via flash chromatography, ethyl acetate/heptane 0% to 100% to afford yellow oil tert-butyl 4-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepane-1-carboxylate (690 mg, 69%).
Reaction SMILES: C[O:2][C:3]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)([OH:14])[C:6]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:5]=2[CH:4]=1.OS(O)(=O)=O.[OH-].[Na+]>CO>[Cl:26][C:24]1[CH:23]=[CH:22][C:6]2[C:7]3([CH:15]4[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]4)[O:14][C:3]([OH:2])([C:13]4[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=4)[CH2:4][C:5]=2[CH:25]=1.[ClH:26]
Reactant: COC1=Cc2cc(Cl)ccc2C(O)(C2CCN(C)CC2)c2ncccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(C23OC(O)(Cc4cc(Cl)ccc42)c2cccnc23)CC1
Product: Cl
Temperature: 25 °C

Procedure:
Dissolve 5-methoxy-8-chloro-11-(1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol (4.26 g) in CH3OH (6 mL) at 0° C. under an argon atmosphere. Add slowly a cooled solution of 92% aqueous H2SO4 (54 mL). Allow the mixture to warm to room temperature for 35 minutes. Pour the solution onto ice, basify with aqueous NaOH (25%), and extract with methylene chloride (3×). Combine the organic portions, wash with brine and dry over sodium sulfate. Filter and concentrate in vacuo. Triturate the residue with isopropyl ether to give an intermediate, 8-Chloro-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5,11-epoxy-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-5-ol as a white solid (3.58 g., 92%, m.p: 170° to 174° C. as HCl salt).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13]([O:15][CH3:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=Cc2ccc(OC)c(OC)c2)C(=O)O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(=Cc1ccc(OC)c(OC)c1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenyl)prop-2-enoic acid (2 g, 6.37 mmol) was dissolved in dimethyl formamide (DMF) (4 mL) and added potassium carbonate (K2CO3) (2.28 g, 16.6 mmol) followed by methyl iodide (CH3I) (0.48 mL, 7.64 mmol) drop wise. The reaction mixture was stirred for 2 hours at room temperature (RT) and the reaction was monitored by TLC. Upon the completion of reaction, K2CO3 was filtered and cold water (100 mL) was added to the filtrate. The resulting precipitate was filtered to get pale yellow solid (2 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12](#[N:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:13][C:12]#[N:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CC#N
Product: COc1ccc(C(O)CC#N)cc1Br

Procedure:
Addition of acetonitrile to 3-bromo-4-methoxybenzaldehyde gave 3-(3-bromo-4-methoxyphenyl)-3-hydroxypropanenitrile as a pale orange oil. Yield (10.32 g, 96%): 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.8, 2.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 5.93 (d, J=4.4 Hz, 1H), 4.85-4.81 (m, 1H). 3.81 (s, 3H), 2.86 (ABd, J=16.4, 4.8 Hz, 1H), 2.79 (ABd, J=16.8, 6.8 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:12]=[CH:11][NH:10][C:9]2[C:5]=1[N:6]=[C:7]([CH:13]([CH3:15])[CH3:14])[N:8]=2)[CH3:2].[CH:16]1([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[CH2:25][Cl:26])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[ClH:26].[CH2:1]([NH:3][C:4]1[N:12]=[CH:11][N:10]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:22]([O:21][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:23]=2)[C:9]2[C:5]=1[N:6]=[C:7]([CH:13]([CH3:14])[CH3:15])[N:8]=2)[CH3:2]
Reactant: COc1ccc(CCl)cc1OC1CCCC1
Reactant: CCNc1nc[nH]c2nc(C(C)C)nc1-2
Solvent: CC#N
Product: CCNc1ncn(Cc2ccc(OC)c(OC3CCCC3)c2)c2nc(C(C)C)nc1-2
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.2 %

Procedure:
6-ethylamino-8-isopropyl-3H-purine (7.52 g, 36.65 mmol) and 3-cyclopentyloxy-4-methoxybenzylchloride (10.59 g, 43.98 mmol) were dissolved in acetonitrile (30 ml) in a high pressure vessel and the resulting mixture heated are 120° C. for 24 hours. On cooling to room temperature a solid precipitated from the solution. The solvent was removed in vacuo, cold water (10 ml) and diethyl ether (100 ml) were added to the solid residue, the mixture stirred vigourously and then filtered. The filter cake was washed with ice-cold ethyl acetate (50 ml) and the solid obtained was oven dried in vacuo at 80° C. to give the title compound (9.51 g, 58%) as a slightly off-white solid. The combined filtrates and washings were concentrated in-vacuo, then water (5 ml) and diethyl ether (100 ml) added, and the mixture treated as before to give further title compound (0.718 g, 5%) as a white solid, m.p.=205-207° C. Combined yield 910.23 g, 63%). Tlc, SiO2 (dichloromethane:methanol, 10:1) Rf=0.49, detection U.V., Dragendorff's reagent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=[O:32].[CH2:33](O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:28]3[CH2:29][CH2:30][CH2:31][CH:26]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:20][C:21]=4[O:32][CH3:33])[C:27]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: CCO
Product: COc1ccccc1C1CCCc2sc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21
Temperature: 25 °C
Yield: 21 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (43 mg, 0.16 mmol) and of crude 2-bromo-6-phenyl-cyclohexanone (49 mg, 0.17 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (15 mg, 21%) as a yellow gum. MS ISP (m/e): 447.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.59 (s, 1H), 7.29 (s, 1H), 7.07-7.18 (m, 2H), 6.82-6.88 (m, 4H), 6.65 (d, 1H), 4.49 (m, 1H), 3.84 (s, 3H), 3.57 (s, 3H), 2.89 (m, 2H), 2.88 (s, 3H), 2.14 (m, 1H), 1.70-1.91 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:41][C:38]2[CH:37]=[CH:36][C:35]([C:34]([O:33][CH3:32])=[O:43])=[CH:40][CH:39]=2)([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (30.12 mmol; 9.62 g) in dry THF (100 mL) under argon at −78° C. was added, dropwise, a 2M solution of lithium diisopropylamide (2M solution in heptanes/THF/ethylbenzene; 39.16 mmol; 19.58 mL). The resulting solution was stirred at −78° C. for 2 hours. 4-Bromomethylbenzoic acid methyl ester (30.12 mmol; 6.90 g) was added and the resulting solution was stirred at −78° C. for 2 hours and allowed to warm to room temperature overnight. Ethyl acetate (150 ml) was added. The resulting solution was washed with a 1M aqueous hydrochloric acid solution (2×50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester. MS (ESI) m/z 468.20 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[N:24][C:23]([C:26](O)=[O:27])=[CH:22][N:21]=3)[C@H:16]([CH3:29])[CH2:15]2)=[C:10]([CH3:30])[C:9]=1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[CH3:48][NH:49][O:50][CH3:51]>C(Cl)Cl.CN(C=O)C>[CH3:51][O:50][N:49]([CH3:48])[C:26]([C:23]1[N:24]=[CH:25][C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[N:13][C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:9]([CH3:31])[C:10]=3[CH3:30])[CH2:15][C@H:16]2[CH3:29])=[N:21][CH:22]=1)=[O:27]
Reactant: CNOC
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(=O)O)cn3)[C@H](C)C2)c1C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 0 °C
Yield: 75.8 %

Procedure:
(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid (50 mg, 0.120 mmol) is dissolved in CH2Cl2 (300 μL). The mixture is cooled to 0° C. and oxalyl chloride (32 μL. 0.358 mmol) is added followed by DMF (3 drops). While stirring, the reaction is warmed to room temperature over 3 h. Diisopropylethylamine (209 μL, 1.2 mmol) is added dropwise followed by addition of N,O-dimethylhydroxylamine hydrochloride (14 mg, 0.144 mmol). Allow the reaction to stir for 16 h. Concentrate the crude mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (42 mg, 76%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>CN(C)C=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:13][C:8]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[C:7]=1[OH:14])=[O:25]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1ccccc1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 61.3 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.32 mmol) and 2-bromophenylisocyanate (47 μL, 0.38 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (20/80, v/v), followed by recrystallization from ethyl acetate and hexane, gave the desired product (88 mg, 62%). EI-MS (m/z) 446.2, 448.3, 450.3 (M−).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[C@@H:20]([NH:19][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Product: NC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (αS)-α-amino-benzeneacetamide hydrochloride (1:1) (CAN 60079-51-8) as starting materials, LC-MS (UV peak area/ESI) 98%, 366.1814 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=O)[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[CH3:30][O:31][NH2:32]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=[N:32][O:31][CH3:30])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCC(CC(C(=O)Nc2cnccn2)c2ccc(S(C)(=O)=O)c(Cl)c2)C1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 73.5 mg, 0.17 mmol) and methoxyamine hydrochloride (21.8 mg, 0.26 mmol) in methanol (512 μL) and pyridine (512 μL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were washed with a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 70% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-methoxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (61.2 mg, 78%) as a white foam: mp 85-87° C.; (ES)+-HRMS m/e calcd for C20H23ClN4O4S (M+H)+ 451.1202. found 451.1207.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[O:17])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C=NCc1ccccc1
Product: O=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=O)NCc1ccccc1

Procedure:
The compound is prepared by a method analogous to that of Example 20 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carboxamide and benzyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15].[CH2:18]=O.O>ClCCCl>[CH3:18][N:12]([CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: NC(CO)CO
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C=O
Solvent: O
Solvent: ClCCCl
Product: CN(Cc1ccc([N+](=O)[O-])cc1)C(CO)CO
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
In 1,2-dichloroethane (75 ml) were suspended p-nitrobenzaldehyde (5 g) and 2-amino-1,3-propanediol (3.0 g), and to the mixture was added, under ice-cooling, triacetoxy sodium boron hydride (9.8 g). Under nitrogen atmosphere, the mixture was stirred at room temperature for 3.5 hours. To the mixture were added, under ice-cooling, 37% formalin (3 ml) and triacetoxy sodium boron hydride (9.8 g), and the mixture was stirred, under nitrogen atmosphere, at room temperature overnight. To the mixture was added water, and the mixture was concentrated. The residue was neutralized with sodium hydroxide solution, saturated with sodium hydrochloride and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column (ethyl acetate) to give 2-(N-methyl-N-(4-nitro-benzyl)amino)-1,3-propanediol (3.0 g) as pale yellow crystals.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](#[N:12])[CH3:11]>>[N:12]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:4][CH2:3][CH2:2][CH2:9][CH2:11][CH2:10]1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC#N
Product: O=Cc1ccc(N2CCCCCC2)cc1

Procedure:
A solution of 4-fluoro-benzaldehyde (2.59 mL, 24.2 mmol) and hexamethyleneimine (8.2 mL, 72 mmol) in acetonitrile (40 mL) was heated at reflux for 16 hours. The product was preabsorbed onto silica gel and purified by flash silica gel chromatography, using ethyl acetate (10-15%) in hexane as the eluant, to give the product, 5.0 g (100%). MS: m/z 204 (MH+). 1H NMR (CDCl3): 1.53-1.59 (m, 4 H), 1.78-1.82 (m, 4 H), 3.53 (t, 4 H), 6.70 (d, 2 H), 7.70 (d, 2 H) and 9.70 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:5]=[N:6][CH:7]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(Cl)C=Cc1cncc(Br)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C=Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 3-(5-bromo-pyridin-3-yl)-acryloyl chloride in the form of unpurified dark brown liquid, N,O-dimethylhydroxylamine hydrochloride (11.6 g, 119.3 mmol), and pyridine (20.4 mL, 252.4 mmol) were added at 0° C. to dichloromethane (150.0 mL). The reaction mixture was stirred at room temperature for 3 hours, quenched with distilled water, and then extracted with dichloromethane. The extract was washed with a 1N hydrochloric acid solution and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was recrystallized from diethyl ether and n-hexane to give 8.2 g of the titled compound as a yellow solid.
Reaction SMILES: [NH2-].[Na+].CO[CH:5]([O:16]C)[CH2:6][CH:7]([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:14])(O)[CH3:12].[CH2:18](Br)[C:19]#[CH:20].C[O:23]CCOC>>[CH3:15][CH:7]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:12])[CH3:14])[CH:6]([O:23][CH2:18][C:19]#[CH:20])[CH:5]=[O:16]
Reactant: COC(CC(C)CCCC(C)(C)O)OC
Reactant: COCCOC
Reactant: C#CCBr
Agent: [NH2-]
Agent: [Na+]
Product: C#CCOC(C=O)C(C)CCCC(C)C
Temperature: 85 °C
Reaction time: 15 h

Procedure:
59 g. of sodium amide (50% suspension in benzene) are placed in 1 liter of 1,2-dimethoxyethane and treated dropwise, while cooling with ice, with 109.2 g. of 1,1-dimethoxy-3,7-dimethyl-7-octanol in 400 ml. of 1,2-dimethoxyethane. The mixture is left to stir under a nitrogen atmosphere for 15 hours at 85°C. The mixture is then again cooled and treated dropwise with a solution of 89.3 g. of propargyl bromide in 250 ml. of 1,2-dimethoxyethane. The mixture is then left to stir at 40°C. until the reaction is complete. The mixture is poured on to 4 liters of ice-water and extracted twice with 2.5 liters of ether. The extracts are washed with 10% sodium hydroxide, water and saturated sodium chloride solution, dried over sodium sulphate and evaporated. By distillation or chromatography, there is obtained pure dimethylacetal of 3,7-dimethyl-(2-propynyloxy)-octanal; boiling point (bulb-tube) = 70°C/0.03 mmHg; nD25 = 1.4491. 65 g. of the dimethylacetal of 3,7-dimethyl-7-(2-propynyloxy)-octanal are heated at 40°C. for 16 hours with a mixture of 300 ml. of 2-N hydrochloric acid, 700 ml. of water and 1 liter of tetrahydrofuran while stirring well. For the working up, the mixture is poured on to 1 liter of ice-water and extracted twice with 1.5 liters of ether. The extracts are washed with 10% sodium carbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and evaporated. By distillation, there is obtained pure 3,7-dimethyl-7-(2-propynyloxy)-octanal; boiling point = 113°C/1 mmHg; nD25 = 1.4553.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[CH:7]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].Br[CH:23]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>CN(C=O)C>[CH2:18]([C:6]1[CH:7]=[C:8]([OH:10])[CH:9]=[C:4]([CH2:1][CH:2]=[CH2:3])[C:5]=1[O:21][CH:23]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25])[CH:19]=[CH2:20]
Reactant: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1O
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCc1cc(O)cc(CC=C)c1OC(C(=O)OC)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2,6-diallyl-4-benzyloxyphenol (200 mg, 1.0 eq) in DMF (8 mL) were added methyl α-bromo-4-chlorobenzeneacetate (190 mg, 1.0 eq) and Cs2CO3 (285 mg, 1.2 eq). The reaction mixture was stirred at room temperature for 15 h, poured into ether, washed with water and brine, dried over MgSO4, filtered, and concentrated in vac. Purification by chromatography (SiO2, EtOAc/Hexanes 1:20) afforded the desired methyl α-(2,6-diallyl-4-hydroxyphenoxy)-4-chlorobenzeneacetate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:24][C:22]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:24][CH3:22])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cnccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the mixture of 4-aminonicotinic acid (691 mg, 5.0 mmol), methylamine hydrogen chloride (410 mg, 1.2 eq), EDC (1.15 g, 1.2 eq), HOBt (810 mg, 1.2 eq) in DMF (20 mL) was added DIEA (3.0 mL, 3.0 eq). The mixture was stirred at room temperature overnight. It was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3 solution. It was concentrated and purified by silica gel with chromatography (0%˜20% MeOH/DCM) to obtain the desired product 4-amino-N-methylnicotinamide.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[Cl:24][C:25]1[CH:30]=[C:29]([NH:31][NH:32][C:33]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)=O)[N:28]=[C:27]([S:40][CH3:41])[N:26]=1.N>C1(C)C(C)=CC=CC=1>[Cl:24][C:25]1[N:26]=[C:27]([S:40][CH3:41])[N:28]2[C:33]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[N:32][N:31]=[C:29]2[CH:30]=1
Reactant: CSc1nc(Cl)cc(NNC(=O)c2ccco2)n1
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: Cc1ccccc1C
Product: CSc1nc(Cl)cc2nnc(-c3ccco3)n12
Temperature: 90 °C
Yield: 78.4 %

Procedure:
In an argon atmosphere, 225 g (1.58 mol) of diphosphorus pentaoxide was suspended in 320 mL of xylene, and 340 mL (256 g, 1.58 mol) of hexamethyldisiloxane was added thereto, followed by heating at 90° C. for about 1.5 hours. After the contents were almost dissolved, 90 g (316 mmol) of Compound A was added thereto, followed by heating at 160° C. for another 2 hours. After completion of the reaction, the reaction solution was cooled, and ice-water was added thereto. Then, the mixture was made alkaline by adding aqueous ammonia under cooling (inner temperature: 5° C. or lower), and was extracted with chloroform. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:1) to obtain 66.1 g of Compound B as a white solid (yield: 78%).