Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([F:14])=[CH:9][N:8]=1.[OH-].[Na+].[CH3:17][O:18][CH2:19]Cl>O.C(OCC)C>[Cl:6][C:7]1[C:12]([O:13][CH2:17][O:18][CH3:19])=[CH:11][C:10]([F:14])=[CH:9][N:8]=1
Reactant: Oc1cc(F)cnc1Cl
Reactant: COCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(F)cnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A DMF (10 ml) solution of 2-chloro-5-fluoro-3-hydroxypyridine (500 mg) was cooled to 0° C. Sodium hydroxide (60% oil dispersion: 149 mg) was added to the reaction solution, and the obtained mixture was stirred at 0° C. for 15 minutes. Chloromethyl methyl ether (293 ul) was added to the reaction solution at the same temperature as described above, and the obtained mixture was heated to room temperature and stirred for 1 hour. Diethyl ether and water were added to the reaction solution, and the organic layer was successively washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1 to 7:3), so as to obtain the title compound (598 mg).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:21]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccccc2)cc1
Yield: 91.8 %

Procedure:
A mixture of alpha-oxo-4-(2-phenoxyethoxy)benzeneacetic acid methyl ester (1.6 g) in methanol (10 mL) and 0.5N sodium hydroxide (30 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl ether-hexane to give 1.4 g of colorless alpha-oxo-4-[[2-(phenoxy)ethyl]oxy]benzeneacetic acid, mp 102°-103° C.
Reaction SMILES: [C:1](Cl)(=[O:13])[O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[C:6]([Cl:12])[CH:5]=1.[CH3:15][N:16]([CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:17]([C:19]1[N:20]=[N:21][NH:22][CH:23]=1)=[O:18].C(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:15][N:16]([CH2:24][CH2:25][CH:26]1[CH2:27][CH2:28][N:29]([C:1]([O:2][CH2:3][C:4]2[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[C:6]([Cl:12])[CH:5]=2)=[O:13])[CH2:30][CH2:31]1)[C:17]([C:19]1[N:20]=[N:21][NH:22][CH:23]=1)=[O:18]
Reactant: CN(CCC1CCNCC1)C(=O)c1c[nH]nn1
Reactant: N#Cc1cc(Cl)cc(COC(=O)Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(C#N)c2)CC1)C(=O)c1c[nH]nn1
Reaction time: 16 h

Procedure:
To 3-chloro-5-cyanobenzyl carbonochloridate (step 4) (65.5 mg, 0.285 mmol) and N-methyl-N-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide (step 3) (78 mg, 0.285 mmol) in DCM (5 mL) was added saturated aqueous sodium bicarbonate solution (5 mL, 0.285 mmol), and the mixture stirred vigorously for 16 hrs. The resulting mixture was acidified with 10% citric acid solution and the organic portion was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in DCM and applied to a 12 g silica cartridge eluting with 0-100% EtOAc/iso-hexane. The product fractions were combined and concentrated to give a gum. This was further purified by UV triggered HPLC, to give 3-chloro-5-cyanobenzyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate as a gum;
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:30])=[CH:32][CH:33]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(C(C)(C)C)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-tert.butylbenzoyl chloride, there is obtained ethyl N-(p-tert.butylbenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a foam, mass spectrum m/e: M+ 426 (8), 398 (6), 194 (100), 161 (36);
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(O)(=O)C>O1CCOCC1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:9]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCc1ccc(C(=CCCCC(=O)O)c2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)CCCC=C(c1ccc(CCNS(=O)(=O)c2ccc(F)cc2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.1 g of 6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoic acid (prepared analogously to Example 10d) are stirred into 150 ml of dioxan with 5 ml of saturated potassium carbonate solution. Then 2.9 g of 4-fluorobenzenesulphonic acid chloride in 20 ml of dioxan are added and the resulting mixture is stirred overnight at ambient temperature. Acetic acid is added and a precipitate is formed. This is separated off and taken up in ethyl acetate, then dried and evaporated down. Finally, the residue is chromatographed over a silica gel column using chloroform/methanol 20:1 as eluant.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10](=[CH2:21])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[C:18]([OH:20])=[O:19])=[O:12]>CN(C=O)C>[Br:8][CH2:21][C@:10]1([CH3:9])[O:19][C:18](=[O:20])[C@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:11]1=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)C(=O)N1CCC[C@@H]1C(=O)O
Solvent: CN(C)C=O
Product: C[C@@]1(CBr)OC(=O)[C@H]2CCCN2C1=O
Reaction time: 20 h

Procedure:
NBS (16 g, 89.9 mmol) was dissolved in DMF (50 ml) and added at room temperature to a solution of (2R)-1-(2-methylacryloyl)pyrrolidine-2-carboxylic acid (11.5 g, contains 8.0 g of the corresponding starting material, 43.4 mmol) in DMF (50 ml). The mixture was stirred for 20 h and evaporated at 80-90° C. The residue was mixed with water (250 ml) and extracted with ethyl acetate (4×80 ml). The combined ethyl acetate phases were washed with 1 M NaHCO3 solution (2×50 ml) and water (1×50 ml). The organic phase was dried over Na2SO4 and evaporated. The yield of the crude oil was 9.3 g. Ethyl acetate (10 ml) was added and the mixture was stirred in an ice bath. The precipitated product was filtered and washed with cooled ethyl acetate. The yield was 1.2 g. 1H NMR (DMSO-d6): 1.58 (3H, s), 1.75-2.10 (3H, m), 2.25 (1H, m), 3.30-3.55 (2H, m), 3.87 (1H, d, J=11.4 Hz), 4.03 (1H, d, J=11.4 Hz), 4.70 (1H, m).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-].ClCCl>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([Cl:1])=[C:15]([OH:20])[CH:14]=[CH:13]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1ccc2cc(Br)ccc2c1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 95.4 %

Procedure:
The compound (S1-2) was synthesized according to the method disclosed in Synlett., No. 18, 2837 (2005). 29.9 g of N-chlorosuccinic acid imide and 600 mL of dichloromethane were added to a reactor under a nitrogen atmosphere and cooled to 0° C., to which 2.6 g of zirconium(IV) chloride was added, and then 50 g of 6-bromo-2-naphthol (S-1) was added gradually. After heating to room temperature and stirred for 10 hours, the reaction mixture was washed with a saturated sodium bicarbonate aqueous solution and water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. 55 g of 6-bromo-1-chloro-2-naphthol (S1-2) was obtained by recrystallization from a mixed solvent of toluene and heptane (1/1 by volume).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:19])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)C=Cc2ccc(F)cc2)cc1
Solvent: CCO
Product: N#Cc1ccc(C(=O)CCc2ccc(F)cc2)cc1

Procedure:
1-(4-cyanophenyl)-3-(4-fluorophenyl)prop-2-en-1-one is hydrogenated in ethanol using 5% Pd-C as a catalyst.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([C@@H:18]2[C@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][NH:20][CH2:19]2)=[O:17])[CH2:12][CH2:11]1.[Cl:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.C=O>>[Cl:30][C:31]1[CH:32]=[C:33]([S:37]([N:20]2[CH2:21][CH2:22][C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:18]([C:16]([N:13]3[CH2:12][CH2:11][N:10]([C:4]4[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=4[CH3:2])[CH2:15][CH2:14]3)=[O:17])[CH2:19]2)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@H]3CNCC[C@H]3c3ccccc3)CC2)c1
Agent: C=O
Agent: Cl
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@H]3CN(S(=O)(=O)c4cccc(Cl)c4)CC[C@H]3c3ccccc3)CC2)c1

Procedure:
In analogy to example 1, step 3, from [4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-((3R,4R)-4-phenyl-piperidin-3-yl)-methanone hydrochloride and 3-chlorobenzene-sulfonyl chloride was prepared [(3R,4R)-1-(3-chloro-benzenesulfonyl)-4-phenyl-piperidin-3-yl]-[4-dimethyl-phenyl)-piperazin-1-yl]-methanone as a white foam, MS: 552.2 ([M+H, 1Cl])+.
Reaction SMILES: [N:1]1([CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.O>[N:1]1([CH:14]([CH2:17][CH3:18])[CH2:15][O:16][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CCC(CO)n1cnc2cnc3ccccc3c21
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC(COCc1ccc(C#N)cc1)n1cnc2cnc3ccccc3c21
Yield: 60.2 %

Procedure:
2-(1H-imidazo[4,5-c]quinolin-1-yl)-1-butanol (3.0 g, 12.4 mmol) was added to a stirring mixture of α-bromo-p-tolunitrile (3.0 g, 15.3 mmol), sodium hydroxide (40 ml, 50%), dichloromethane (40 ml), and benzyltrimethylammonium chloride (0.02 g, 0.11 mmol). The reaction was maintained for 72 hours and then diluted with dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase was extracted with additional dichloromethane (100 ml). The organic fractions were combined, washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9/1 dichloromethane/methanol, Rf 0.48) to provide 2.66 g of 4-{[2-(1H-imidazo[4,5-c]quinolin-1-yl)butoxy]methyl}benzonitrile.
Reaction SMILES: CS([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:6]=1)(=O)=O.[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:38]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:6]=1)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CS(=O)(=O)c1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
4'-Methanesulfonyl-2,2':6',2"-terpyridine (4.67 g, 0.015 mol) and hexadecyl alcohol (2,42 g, 0.010 mol) were added to N,N-dimethylformamide (0.1 liter). At 15° C., sodium hydride (60% content, oil dispersion, 0.8 g) was added thereto over a period of about 10 minutes. The entire solution was stirred for 30 minutes and then the reaction mixture was reacted under reflux for 4 hours. After cooling to room temperature, the reaction mixture was poured into an aqueous 4M sodium chloride solution (0.3 liter). The crystal that precipitated was taken out by filtration under suction and then washed with water and hexane. The crystal was again dissolved in chloroform and washed with 1M hydrochloric acid and water. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The resulting crystal was recrystallized from hexane to obtain 4.36 g of the above-entitled product (T-6). Yield: 92%. m.p. 97.5 to 99.0° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[CH:2]1.[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:14])=[CH:2]1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)/C=C/c1c[nH]c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1H-indol-3-yl)acrylic acid (200 mg, 1.06 mmol), N′-isopropylbenzohydrazide (283.4 mg, 1.59 mmol) and HATU (604.6 mg, 1.59 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.277 ml, 1.59 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=15:3:1) and dried so that white solid form of (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained (327 mg, 88%).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)N(C)c3ccccc3)c2c1C

Procedure:
Using the methods of Examples 75-85, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 367.2263.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6](/[CH:11]=[C:12](\[O-])/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:4][N:3]=1.[K+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8][C:7]=12
Reactant: CCOC(=O)/C([O-])=C/c1ccnc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccnc(Cl)c2[nH]1
Temperature: 60 °C
Reaction time: 18.5 h
Yield: 72 %

Procedure:
Potassium (1Z)-1-(2-chloro-3-nitropyridin-4-yl)-3-ethoxy-3-oxoprop-1-en-2-olate (19.8 g, 63.6 mmol) was dissolved in acetic acid (908 mL) and the solution was treated with iron powder (14.6 g, 280.9 mmol). The reaction mixture was warmed to 60° C. and stirred overnight (18.5 h). TLC analysis indicated consumption of the starting material, therefore the reaction mixture was filtered through diatomaceous earth to remove the catalyst. The filtrate was concentrated to dryness. The residue was treated with methylene chloride (ca. 400 mL) and filtered through a plug of silica. Eluting with methylene chloride removed insolubles, and further elution with methylene chloride/ethyl acetate (50:50) provided ethyl 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (10.3 g, 45.8 mmol, yield 72%) as a yellow solid after concentration: Rf 0.80 (silica gel, 50:50 hexanes/ethyl acetate); mp 152-157° C.; 1H NMR (300 MHz, CD3OD) δ1.43 (3H, t, J=7.0 Hz), 4.44 (2H, q, J=7.1 Hz), 7.27 (1H, s), 7.65 (1H, d, J=5.7 Hz), 7.95 (1H, d, J=5.4 Hz); ESI MS m/z 224 [C10H9ClN2O2+H]+; HPLC (Method A) >99% (AUC), tR=16.6 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][CH2:15]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: OCCC1CN(Cc2ccccc2)CCO1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCC1CN(Cc2ccccc2)CCO1
Yield: 121.1 %

Procedure:
To 200 ml of toluene is added 58 g of a solution of 70% RDB in toluene and to the mixture is added dropwise a solution of 26.3 of ethyl 4-benzyl-2-morpholinylacetate in 50 ml of toluene below 10° C. Further, after ice-cooling for 30 minutes, the mixture is stirred at room temperature overnight. After to the reaction mixture is successively added 20 ml of acetone and 100 ml of water, the inorganic substance precipitated is filtered off. The toluene layer is separated from the filtrate and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure and the residue is purified by chromatography on silica gel to give 10.1 g of 2-(4-benzyl-2-morpholinyl)ethanol. To a mixture of 2.21 g of 2-(4-benzyl-2-morpholinyl)ethanol in 30 ml of chloroform is added 2.30 g of thionyl chloride and the system refluxed for 2.5 hours. After completion of the reaction, the solvent is concentrated under reduced pressure and to the residue are added water and ether. After neutralizing with potassium carbonate, the ether layer is separated and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure to give 2.90 g of 2-(2-chloroethyl)-4-benzylmorpholine as an oily substance.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:45]=[C:44]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH:43]=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[N:45]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc(N2CCOCC2)n1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccc(N4CCOCC4)n3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 53.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.65 g) and 6-chloromethyl-2-morpholinopyridine (0.29 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-morpholinopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Cl[C:37]([O:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38]>>[F:42][C:41]([F:44])([F:43])[CH2:40][O:39][C:37]([N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=3[C:32]([F:35])([F:34])[F:33])[N:8]=[CH:9]4)[C:18](=[O:29])[N:19]=2)[CH2:23][CH2:24]1)=[O:38]
Reactant: O=C(Cl)OCC(F)(F)F
Reactant: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: O=C1N=C(N2CCCN(C(=O)OCC(F)(F)F)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepane-1-carboxylic acid 2,2,2-trifluoro-ethyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one and 2,2,2-Trifluoroethyl chloroformate according to Example 133.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[CH:12][N+:13]([O-])=O)[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[BH4-].[Na+].C(O)(=O)C(O)=[O:28]>O.C(O)(C)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([CH2:12][NH2:13])[CH2:9][N+:8]([O-:28])=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: O=[N+]([O-])C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: NCC1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reaction time: 2 h

Procedure:
To 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine (IV, J. Heterocyclic Chem., 13, 433 (1976)--compound 4b, 40 g, 115 mmol) and sodium borohydride (6.68 g, 176 mmol, 10 mesh) is added THF (100 ml) and i-propyl alcohol (50 ml). The resulting slurry is treated with a slow addition of water (3.1 ml, 176 mmol) while the temperature is maintained at about 23°. The reaction mixture is stirred for 2 hr. Water (9.3 ml) is added slowly to quench the reaction mixture. Methanol (50 ml) is used to facilitate transfer of the reaction mixture to a 500 ml capacity stainless steel Buchi hydrogenator. Raney nickel (40 g of water wet material) is added and the hydrogenation is performed at 5° and 60 psig pressure. After 17 hr, HPLC showed the reduction is complete. The reaction mixture is removed from the Buchi and the hydrogenator is rinsed with methanol (200 ml). The combined reaction mixture and rinses are filtered through a 5 g pad of solka floc to remove spent catalyst. The catalyst cake is then rinsed with methanol (200 ml). The combined filtrate and rinses are concentrated. Water is added to the concentrate. The product is extracted from the aqueous layer using ethyl acetate (200 ml). The ethyl acetate extract is concentrated to near dryness to azeotrope any residual water. Finally, ethyl acetate (600 ml) is used to dissolve the crude product and the mixture is heated to 50-60°. Then oxalic acid (10.36 g, 115 mmol) is added. The slurry that forms is stirred overnight at 20-25° and is then cooled to 0° for 1 hr and the product is collected by vacuum filtration. The product is washed with ethyl acetate (100 ml) and dried at 40° in a vacuum oven to give the title compound as the oxalic salt, mp=144-148°; TLC (methylene chloride/methanol/ammonium hydroxide, 90/10/1) Rf =0.17.