Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=[CH:2]1.Cl.O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O.Cl>CO>[N:12]1([C:3]2[C:4]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:1][CH:2]=2)[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1
Reactant: c1cnc2cc[nH]c2c1
Reactant: O=C1CCCCN1
Agent: Cl
Solvent: O
Solvent: CO
Product: C1=CCN(c2c[nH]c3cccnc23)CC1

Procedure:
To a stirred solution of Na (2.53 g, 110 mmol, 11 eq) in absolute methanol (50 ml) at room temperature was added the appropriate pyrrolopyridine (10.00 mmol) and piperidone monohydrate hydrochloride (4.60 g, 30.0 mmol, 3.0 eq). The resultant mixture was then heated at reflux under nitrogen for 2-24 hours depending on the substrate. The resultant reaction mixture was cooled, and concentrated hydrochloric acid (37%, 9.0 ml, 110 mmol) wasadded dropwise with vigorous stirring. The resultant mixture was then evaporated under reduced pressure, and the residual slurry placed in water(50 ml). This aqueous mixture was extracted with ethyl acetate (5×50 ml), and these extracts were combined, dried (Na2SO4), and evaporated under reduced pressure. The residue was either triturated directly or column chromatographed using silica gel (approximately 100 g) and elution with the appropriate solvent system yielding the desired 3-(1,2,5,6-tetrahydropyridyl)pyrrolopyridine, one of Compounds 1a-1m or compound 2, 3a, 3b, 3c or 4.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]([O:18]CC)=[O:17])[N:14]=[CH:15][N:7]2[C:6]2[CH:21]=[CH:22][S:23][C:5]1=2>C(O)C.O>[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]([OH:18])=[O:17])[N:14]=[CH:15][N:7]2[C:6]2[CH:21]=[CH:22][S:23][C:5]1=2
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Yield: 88.2 %

Procedure:
13.9 ml (55.6 mmol) of 4N sodium hydroxide solution were added dropwise to a suspension of 13.5 g (44.5 mmol) of ethyl (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylate in 10 ml of ethanol and 16 ml of water. The mixture was heated at reflux for 30 minutes and the ethanol was subsequently distilled off. The aqueous phase was washed twice with methylene chloride and adjusted to pH=3 with 4N hydrochloric acid. The resulting precipitate was filtered off and washed with water, ethanol and subsequently with diethyl ether. There were obtained 10.8 g (88%) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid as a colourless powder of m.p. 260° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](C)[CH:6]=[CH:5][C:4]=1[S:10]([NH2:13])(=[O:12])=[O:11].[C:14]([O-:17])(O)=[O:15].[Na+].[O-][Mn](=O)(=O)=O.[K+]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[S:10](=[O:12])(=[O:11])[NH2:13])[C:14]([OH:17])=[O:15]
Reactant: COc1cc(C)ccc1S(N)(=O)=O
Reactant: O=C([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)O)ccc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
2-Methoxy-4-methyl-benzenesulfonamide (201 mg, 1 mmol) was dissolved in H2O (10 mL). NaHCO3 (67 mg, 0.8 mmol) and KMnO4 (653 mg, 4.13 mmol) was added. The reaction mixture was stirred at reflux for 4 h. The reaction mixture was cooled to rt and filtered. the filtrate was acidified to pH=2 using conc. HCl. The precipitate was collected by filtration, washed with H2O affording the title compound as a white powder (117 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]#[N:22]>CC(C)=O>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]=1[O:11][CH2:20][C:21]#[N:22])=[O:8]
Reactant: CN(C)c1ccc(C=O)c(O)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)c1ccc(C=O)c(OCC#N)c1

Procedure:
82 parts of 4-dimethylaminosalicylaldehyde is dissolved in 500 parts by volume of acetone, then 96 parts of potassium carbonate and 45 parts of chloroacetonitrile are added and the whole is boiled under reflux for 10 hours. After the solution has been filtered it is concentrated and the crystals deposited are recrystallized from benzene with the addition of animal charcoal. 36 parts of colorless crystals of 2-formyl-5-dimethylaminophenoxyacetonitrile is obtained with a melting point of 124° to 125°C.
Reaction SMILES: [CH3:1][C:2]([NH2:14])([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[N:15]1[N:16]=[N:17][N:18]2[CH:23]=[C:22]([C@@H:24]3[CH2:26][O:25]3)[CH:21]=[CH:20][C:19]=12>C(O)C>[CH3:13][C:2]([NH:14][CH2:26][C@@H:24]([C:22]1[CH:21]=[CH:20][C:19]2[N:18]([N:17]=[N:16][N:15]=2)[CH:23]=1)[OH:25])([CH3:1])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(N)Cc1c[nH]c2ccccc12
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: CC(C)(Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc2nnnn2c1

Procedure:
A solution of 670 mg (3.58 mmol) of (1,1-dimethyl-2-(1H-indol-3-yl)ethyl amine (B. Heath-Brown and P. G. Philpott, J. Chem. Soc., 7165 (1965)) and 598 mg (3.69 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane in 12 ml of absolute ethanol was heated at reflux for 15 hours. The reaction mixture was concentrated and the residue (1.24 g) chromatographed on silica gel (95:5:1 CH2Cl2 :MeOH:conc. NH4OH) to give 808 mg of (R)-α-[[(1,1-dimethyl-2-(1H-indol-3-yl)ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[C:12]([Cl:18])[CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:1]([NH:8][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][C:12]=1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(Br)ccc1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
765 μl of benzylamine are dissolved in 10 ml of THF (anhydrous) and treated with 1.0 g of 4-bromo-1-bromomethyl-2-chlorobenzene at 0° C. and stirred at RT for 4 h. 100 ml of a half-saturated aqueous Na2CO3 solution are then added and the mixture is extracted three times with 100 ml of EA each time. It is dried over MgSO4 and chromatographed on silica gel using DIP. 590 mg of a colorless oil are obtained.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]1[C:21]2[CH:22]=[CH:23][O:24][C:20]=2[C:19]([Cl:25])=[CH:18][CH:17]=1>C1COCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:15][C:16]1[C:21]2[CH:22]=[CH:23][O:24][C:20]=2[C:19]([Cl:25])=[CH:18][CH:17]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Clc1ccc(CBr)c2ccoc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(Cl)c2occc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl malonate (1.7 ml) was added dropwise to a suspension of sodium hydride (60%; 0.3 g) in dry THF (40 ml) at 0° under nitrogen. The mixture was allowed to warm to room temperature over 15 mins. Then a solution of 4-bromomethyl-7-chloro-benzofuran in dry THF (10 ml) was added in one portion and the mixture stirred for 1 h; then partitioned between water (100 ml) and ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4) and evaporated to give the title compound as a pale yellow oil (2.466 g)
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.[CH3:26][O:27][C:28](=[O:34])[CH:29](O)[CH:30]([CH3:32])[CH3:31].CO>C(OCC)(=O)C>[CH3:26][O:27][C:28](=[O:34])[CH:29]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH:30]([CH3:32])[CH3:31]
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: COC(=O)C(O)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(C)C

Procedure:
Following the procedures of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol and 2-hydroxy-3-methyl-butyric acid methyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give racemic 3-Methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid methyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=3.70 min, [M+H]+=466
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:12])[C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:24]=[CH:25][CH:26]=[N:27]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:12][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[CH3:11])[C:5]([NH:27][CH:26]1[CH2:24][CH2:25]1)=[O:7]
Reactant: Cc1c(Br)cc(C(=O)O)cc1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Br)cc(C(=O)NC2CC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dibromo-4-methylbenzoic acid (1 eq.) in DMF (0.4 M) was added HATU (1.3 eq.), cyclopropylamine (1.1 eq.) and Hunig's base (3 eq.). The resulting yellow mixture was stirred at RT for 18 h. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Trituration of the crude product thus obtained in a mixture of ether and hexanes afforded the title compound as an off-white solid.
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([NH:7][C:8]([O:10]C(C)(C)C)=O)=[CH:5][CH:4]=1)#N.S.[C:18]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[S:34])[NH2:33])=[CH:28][CH:27]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>N1C=CC=CC=1.CO>[C:21]([O:20][C:18](=[O:19])[NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[S:34][CH:16]=[C:3]([C:4]3[C:8](=[O:10])[NH:7][C:6]4[C:5]([CH:5]=3)=[CH:4][CH:3]=[CH:16][CH:15]=4)[N:33]=2)=[CH:30][CH:31]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(N)=S)cc1
Agent: S
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(-c3cc4ccccc4[nH]c3=O)cs2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-cyano-tert-butyloxycarbonylaniline (2.20 g, 10.0 mmol) in 20 mL of pyridine and 5 mL of TEA was purged with H2S gas for 7.0 h. Solvents were removed under vacuum. The resulting crude 4-Boc-aminobenzene-thiocarboxamide (yellow residue, 70% purity) was used directly in the next step. A solution of 4-Bocamino-benzenethiocarboxamide (205 mg, 70% pure, 0.57 mmol) and 3-(2-bromoacetyl)hydroquinolin-2-one (Example 27b, 78 mg, 0.29 mmol) in 50 mL of MeOH was heated at reflux for 4 h. After cooling to RT, the precipitates were collected by filtration to provide the title compound as an off-white solid. MS m/z: 420.2 (M+1). HRMS m/z: 420.1358 (M+H+, C23H21N3O3S Calc'd 420.1376).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]([CH2:12]Cl)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[Cl:2][C:3]1[N:4]([CH2:12][S:21][C:19]2[N:18]=[C:17]([OH:22])[CH:16]=[C:15]([CH3:14])[N:20]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: ClCn1nc2ccccc2c1Cl
Reactant: Cc1cc(O)nc(S)n1
Agent: [Ag+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCn2nc3ccccc3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
3-chloro-2-(chloromethyl)-2H-indazole hydrochloride (285 mg, 1.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (142 mg, 1.0 mmol), and silver carbonate (550 mg, 2.0 mmol) were mixed in acetone (20 mL). The mixture was stirred at room temperature overnight. The solid was filtered. The solution was evaporated, and the crude product was purified by column chromatography to provide the titled final product (15 mg, 5% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.34 (s, 3H), 6.05 (s, 1H), 6.22 (s, 2H), 7.25 (t, 1H), 7.48 (t, 1H), 7.67 (d, 1H), 7.74 (s, 1H); M+ 307.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][C:6]#[CH:7].I[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=1>C1COCC1.C(NC(C)C)(C)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][C:6]#[C:7][C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:23][CH:22]=1
Reactant: C#CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Ic1ccc(Oc2ncccn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC#Cc1ccc(Oc2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Under an argon atmosphere, copper iodide (2.8 mg) and dichlorobis(triphenylphosphine)palladium (5.2 mg) were added to a solution of 2-(2,6-dichlorobenzamido)pent-4-ynoic acid methyl ester (74 mg) and 2-(4-iodophenoxy)pyrimidine (81 mg) in THF/diisopropylamine (3/1) mixture (5 ml), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and ethyl acetate was added to the residue. The insoluble matter was removed by filtration, and the filtrate was washed once with water and once with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→cyclohexane/chloroform=1/3) to obtain 2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yloxy)phenyl]pent-4-ynoic acid methyl ester (100 mg).
Reaction SMILES: C(Cl)(Cl)Cl.[CH:5]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[C:26]2=[O:37])[CH2:20][CH2:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CO>[CH:5]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[CH:26]2[OH:37])[CH2:20][CH2:19]1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2c(c1)CCC(CN1CCN(C(c3ccccc3)c3ccccc3)CC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)CCC(CN1CCN(C(c3ccccc3)c3ccccc3)CC1)C2O

Procedure:
In a mixture of 50 ml. of chloroform and 100 ml. of methanol is dissolved 3.5 g. of 2-(4-benzhydryl-1-piperazinylmethyl)-6-methoxy-3,4-dihydro-1(2H)-naphthalenone. Following the addition of 3 g. of sodium borohydride, the solution is stirred at room temperature for 30 minutes. The reaction mixture is then diluted with 500 ml. of water and extracted with chloroform. The extract is dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby 3 g. of 2-(4-benzhydryl-1-piperazinylmethyl)-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenol is obtained as oily residue. This residue is dissolved in a mixture of 20 ml. of 20 % ethanolic hydrochloric acid and 30 ml. of ethanol, and the solution is heated at 80°-90°C. for 30 minutes. The reaction mixture is cooled to obtain 2.7 g. of 3-(4-benzhydryl-1-piperazinylmethyl)-7-methoxy-1,2-dihydronaphthalene hydrochloride as colorless needles melting at 220°-235° C. (gradually decomposed).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17](Cl)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:27]#[N:28])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(Cl)nn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(C#N)nn2)CC1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To a mixture of zinc cyanide (0.077 g, 0.66 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.1 g, 0.09 mmol) was added a solution of 4-(6-chloro-5-phenyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D13) (0.137 g, 0.36 mmol) in N,N-dimethylformamide (3.5 ml). The resulting mixture was stirred at 160° C. for 30 min, under microwave irradiation. The solvent was evaporated in vacuo to yield D14 (0.133 g, quant.). C20H23N5O2 requires 365; Found 366 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH3:16])[C:12]([OH:14])=O.Cl.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[OH:28]>>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH2:19][NH:18][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH3:16])=[C:21]([OH:28])[CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(CN)c(O)c1
Reactant: COc1cc(F)c(C(OC)C(=O)O)c(F)c1
Agent: Cl
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2O)c(F)c1

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-methoxy-acetic acid (example 66.1) was coupled with 4-aminomethyl-3-hydroxy-benzonitrile hydrochloride (example 110.2) according to general procedure C to give (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Colorless foam. MS 361.1 ([M−H]−)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[N:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[F:16])[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2C(=O)CC1C
Reactant: Nc1ccccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2C(=Nc2ccccc2F)CC1C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
[Step 1] 50 mg of 1-acetyl-4-oxo-2-methyl-1,2,3,4-tetrahydroquinoline and 83 mg of 2-fluoroaniline were dissolved in 2 mL of toluene, and 125 μL of titanium tetrachloride (1.0 M dichloromethane solution) was added to the solution under ice cooling. The resulting mixture was stirred for one hour under ice cooling, and then was stirred for 3 hours at 80° C. After completion of the reaction, the reaction liquid was filtered through Celite and was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (diethyl ether:hexane=2:1), and thus 60 mg (81%) of 1-acetyl-2-methyl-4-[(2-fluorophenyl)imino]-1,2,3,4-tetrahydroquinoline was obtained as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C@H:25]5[CH2:29][CH2:28][CH2:27][NH:26]5)[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH2:32]=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C@H:25]5[CH2:29][CH2:28][CH2:27][N:26]5[CH3:32])[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(OC[C@H]2CCCN2)n1
Reactant: C=O
Solvent: CO
Solvent: ClCCl
Product: CN1CCC[C@@H]1COc1cccc(Cn2ncc3cc(-c4ccc(Cl)cc4)sc3c2=O)n1

Procedure:
2-(4-Chlorophenyl)-6-({6-[(2R)-pyrrolidin-2-ylmethoxy]pyridin-2-yl}methyl)thieno[2,3-d]pyridazin-7(6H)-one (0.340 g, 0.75 mmol), formaldehyde(aq.) 36% (0.23 mL, 2.25 mmol) and MacroPorous-triacetoxyborohydride (0.88 g, 2.25 mmol) were shaked in DCM/MeOH (1:1, 4 mL) at room temperature for 3 hours. The reaction mixture was filtrated, concentrated in vacuo and purified by flash chromatography using a gradient with EtOAc:MeOH:TEA (1:0.1:0.01) in n-heptane, which gave the product as an solid. Yield: 0.207 g (59%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.55-7.61 (m, 2H), 7.37-7.48 (m, 4H), 6.69 (d, 1H, J=7.27 Hz), 6.59 (d, 1H, J=8.26 Hz), 5.45 (s, 2H), 4.21-4.27 (m, 1H), 4.06-4.14 (m, 1H), 2.97-3.04 (m, 1H), 2.41-2.52 (m, 1H), 2.34 (s, 3H), 2.11-2.21 (m, 1H), 1.78-1.91 (m, 1H), 1.54-1.78 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 163.7, 157.4, 153.9, 152.3, 140.3, 139.2, 136.6, 136.0, 133.3, 131.4, 129.8, 128.2, 118.9, 114.3, 110.0, 68.3, 64.4, 57.9, 56.0, 41.8, 28.7, 23.1. MS (ESI+) 467.0 (M+1H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:21])[N:17]=[C:18](Cl)[CH:19]=[C:11]12)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30][OH:31])[CH:26]=[CH:27][C:28]=1[F:29]>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:21])[N:17]=[C:18]([O:31][CH2:30][C:25]3[CH:26]=[CH:27][C:28]([F:29])=[C:23]([F:22])[CH:24]=3)[CH:19]=[C:11]12)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=c1nc(Cl)cc2n1CCCN2Cc1ccccc1
Reactant: OCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1nc(OCc2ccc(F)c(F)c2)cc2n1CCCN2Cc1ccccc1
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a suspension of NaH (21.76 mg, 0.54 mmol) in N,N-dimethylformamide (DMF) (2 mL), 1-benzyl-8-chloro-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (50 mg, 0.18 mmol) was added (3,4-difluorophenyl)methanol (0.026 mL, 0.22 mmol) at r.t., and stirred for 30 mins. The reaction mixture was quenched by water. Purification via reverse phase column (0.3% trifluoroacetate acid in acetonitrile/water) afforded the title compound (22 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2cc(Cl)ncn2)CC1

Procedure:
A solution of 4,6-dichloropyrimidine (5.22 g), ethyl isonipecotate (5.50 g) and triethylamine (7 ml) in ethanol (60 ml) was stirred at room temperature for 2 hours, and solvent removed in vacuo. The crude mixture partitioned between ethyl acetate (100 ml) and water (50 ml), washed with brine, dried (MgSO4) and solvent removed to give 1-(6-chloropyrimidin-4-yl)-4-(ethoxycarbonyl)piperidine.