Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH2:27][CH2:28][CH2:29][OH:30]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][NH:27][CH2:28][CH2:29][OH:30])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CNCCO)CC2

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), 2-aminoethanol (0.5 ml), ACN (3 ml). 1H-NMR (400 MHz, CDCl3): δ 7.37-7.39 (2H, m), δ 7.23 (1H, d, J=8 Hz), δ 4.18-4.24 (1H, m), δ 3.63-3.72 (2H), δ 3.02 (3H, s), δ 2.81-3.00 (6H, m), δ 1.97-2.08 (1H, m), δ 1.83-1.87 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[CH:26]=[N:27][C:28]([O:31]C)=[CH:29][CH:30]=2)=[N:4][C:5]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1>O1CCOCC1.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:12][CH2:13]2)=[O:10])=[N:4][C:3]=1[C:25]1[CH:30]=[CH:29][C:28](=[O:31])[NH:27][CH:26]=1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(-c2ccc(=O)[nH]c2)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 90 °C
Yield: 22.4 %

Procedure:
N-(3-Chloro-6′-methoxy-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (124 mg, 0.270 mmol) was dissolved in a mixture of 1.2 mL of 1,4-dioxane and 0.6 mL of 4M aqueous hydrochloric acid. This solution was heated at 90° C. for 5 hours. The crude reaction mixture was quenched with triethylamine and then evaporated to dryness. The crude product was then partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate, and then purified on 4 g of silica gel utilizing a gradient of 0-5% methanol in dichloromethane to yield N-(5-chloro-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a white solid (27 mg, 22%). ESI-MS m/z calc. 445.1. found 445.9 (M+1)+. Retention time 1.62 minutes.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[F:6][C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1>O.Cl.C(OCC)C>[N:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=1)=[N+:14]=[N-:1]
Reactant: O=N[O-]
Reactant: NNc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
Sodium nitrite (262 mg) dissolved in 1.0 ml of water was dropped, under cooling with ice, into a solution of 500 mg of 3-fluorophenylhydrazine hydrochloride in 2.5 ml of concentrated hydrochloric acid and 3.0 ml of diethyl ether. Temperature of the reaction solution was raised to room temperature followed by stirring for 3 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 252 mg of the title compound as a brown oily crude product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.O>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: COCCl
Reactant: Cc1cc(C)c(C=O)c(O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCOc1cc(C)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-hydroxy-4,6-dimethylbenzaldehyde (0.75 g) and diisopropylethylamine (1.4 mL) in dichloromethane (20 mL) was added chloromethyl methyl ether (0.57 mL), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=20/1) to give 2-(methoxymethyloxy)-4,6-dimethylbenzaldehyde (0.57 g).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[C:13]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([NH2:25])=[S:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CC(C)=O>[C:13]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]2[S:24][CH:2]3[CH2:10][C:9]4[CH:8]=[C:7]([Cl:11])[CH:6]=[CH:5][C:4]=4[C:3]3([OH:12])[N:25]=2)=[CH:19][CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: CC(C)(C)c1ccc(OCC(N)=S)cc1
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(OCC2=NC3(O)c4ccc(Cl)cc4CC3S2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At room temperature, 0.49 g of 2-bromo-5-chlorindan-1-on and 0.45 g of 2-(4-tert-butylphenoxy)-thioacetamide were dissolved in 10 ml of dry acetone, and the mixture was stirred at room temperature for 12 h. The precipitated hydrobromide was filtered off with suction and washed with acetone. The residue was suspended in a little ethyl acetate and treated with saturated sodium bicarbonate solution. The organic phase was separated off, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This synthesis yielded 2-(4-tert-butylphenoxymethyl)-6-chloro-8,8a-dihydroindeno [1,2-d]thiazol-3a-ol having a melting point of 122-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48].[C:49](Cl)(=[O:51])[CH3:50]>C(N(CC)CC)C.ClCCl>[C:49]([NH:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])(=[O:51])[CH3:50]
Reactant: CC(=O)Cl
Reactant: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1NC(C)=O
Reaction time: 2 h

Procedure:
The solution of 0.380 g of tert-butyl 3-[4-amino-3-(3-methoxypropoxy)benzyloxy]4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 0.168 ml of triethylamine and 10.0 ml of dichloromethane is cooled to 0° C. and admixed slowly with the solution of 0.090 ml of acetyl chloride in 1.0 ml of dichloromethane. The reaction solution is stirred over 2 hours, poured onto ice-water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with successively with water (20 ml) and brine (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (1:1 EtOAc-heptane); Rt=5.73.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[CH:3]=1.C([Li])CCC.C[O:24]B(OC)OC.Cl>O1CCCC1>[CH2:10]([O:9][C:5]1[C:4]([CH3:17])=[CH:3][C:2]([OH:24])=[CH:7][C:6]=1[Cl:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(Br)cc(Cl)c1OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(O)cc(Cl)c1OCc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Then, 40 g of 4-bromo-6-chloro-2-methyl-1-benzyloxybenzene was dissolved in 400 ml of tetrahydrofuran, followed by stirring at -70° C., to which 76 ml of n-butyl lithium solution (in hexane, 1.69 mol/liter) was added dropwise, followed by further stirring at -70° C. for 2 hours. To this reaction mixture was added dropwise a solution of 13.3 g of trimethoxyborane dissolved in 50 ml of tetrahydrofuran. Then, the reaction mixture was stirred for 1 hours, while warming to room temperature, and 100 ml of 10% aqueous hydrochloric acid solution was added in small portions, followed by stirring for 20 minutes. The tetrahydrofuran layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was mixed with 200 ml of toluene, and heated at 70° C. under stirring, to which 36 ml of 30% aqueous hydrogen peroxide solution was added dropwise. After heating under reflux for 1 hour, the reaction mixture was washed once with water, twice with 10% ferrous sulfate and then ammonium water, and once with water, followed by phase separation. The toluene layer was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 29 g of 4-benzyloxy-3-chloro-5-methylphenol (91% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([S:18][CH3:19])=[N:14][CH:15]=3)[N:10]([CH3:20])[C:9]2=[O:21])=[CH:4][C:3]=1[N+:22]([O-])=O>CO.[Pd]>[NH2:22][C:3]1[CH:4]=[C:5]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([S:18][CH3:19])=[N:14][CH:15]=3)[N:10]([CH3:20])[C:9]2=[O:21])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c([N+](=O)[O-])c1)C2
Agent: [Pd]
Solvent: CO
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(N)c1)C2
Yield: 65.5 %

Procedure:
To a solution of 3-(4-fluoro-3-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (3.0 g, 8.6 mmol) in MeOH (30 mL) was added 10% Pd/C (1.2 g, 1.1 mmol). The resultant mixture was stirred overnight under H2 (30 psi). The mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography to give 3-(3-amino-4-fluorophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.8 g, 66% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 8.21 (s, 1 H), 6.99 (dd, J=6.6, 8.4 Hz, 1 H), 6.70 (dd, J=1.8, 6.0 Hz, 1 H), 6.47 (m, 1 H), 5.21 (br s, 2 H), 4.65 (s, 2 H), 3.26 (s, 3 H), 2.50 (s, 3 H); MS (ESI) m/z: 320.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[C:33]([O:34][CH3:35])=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2ccccc2cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Product: COc1cc2ccccc2cc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Example 3 (c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3 (b)] with 2-bromomethyl-3-methoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[3-methoxy-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate as a colourless resin; MS: 465 (M)+.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:6]=1/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([CH3:3])[CH3:2].C(N(CC)CC)C>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH:1]([S:4][C:5]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:6]=1[CH:7]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][NH:8]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCC/N=C/c1cc([N+](=O)[O-])ccc1SC(C)C
Agent: [Ti+4]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCNC1c1cc([N+](=O)[O-])ccc1SC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
To 20B (12.0 g, 28.2 mmol) and triethylamine (7.86 mL, 56.4 mmol) in dichloromethane at −10° C. was added titanium chloride (113 mL, 1 M in dichloromethane) dropwise under argon. The reaction was stirred at rt for 4 h and then quenched with saturated potassium carbonate. The mixture was filtered through celite and the aqueous layer was extracted with dichloromethane (2×). The organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was evaporated to give 7.3 g of crude pyrrolidine 20C.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][N:16]([CH3:26])[C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH3:15][N:16]([CH3:26])[C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: CN(C)c1cccc(B(O)O)c1
Product: CN(C)c1cccc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 60.8 %

Procedure:
6-[3-(Dimethylamino)phenyl]-5-phenyl-1,2,4-triazin-3-amine (53 mg, 60%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-(dimethylamino)phenylboronic acid (56.7 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].[SiH4].[Cl-].[Na+]>CO>[CH3:1][O:2][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8]
Reactant: C[O-]
Reactant: CO[Si](CCl)(OC)OC
Agent: [Cl-]
Agent: [Na+]
Agent: [SiH4]
Solvent: CO
Product: COC[Si](OC)(OC)OC
Reaction time: 0.5 h

Procedure:
340 g (6.3 mol) of sodium methylate (95% strength) are dissolved in portions in 2.5 l of methanol in a laboratory reactor blanketed with nitrogen. During this procedure, the solution heats up to 65° C. Thereafter, 995 g (5.8 mol) of chloromethyltrimethoxysilane are added dropwise over 1.5 h and stirring is effected for a further 30 minutes at the boil. On addition of the silane, sodium chloride is precipitated spontaneously as the salt, but the suspension remains readily stirrable until the end of the metering. The precipitated sodium chloride is filtered off with suction and the methanol is removed under a partial vacuum at 40–50° C. The residue is purified by distillation (97–98° C. at 172 mbar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[OH-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C1(C)C=CC=CC=1.O>[C:10]([C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)#[N:11]
Reactant: COc1ccc(CC#N)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
4-Methoxyphenylacetonitrile (7.63 g, 50 mmol) in toluene (30 mL), PEG(E)-400 (4 g, 10 mmol) and 52% aqueous sodium hydroxide (10.73 g in 12.4 mL water) were placed in a flask equipped with a magnetic stirrer. 4-Nitrobenzaldehyde (7.56 g, 50 mmol) in a minimum of toluene was added dropwise. The mixture was stirred for 1 h at 20° C. and then diluted with water (30 mL). The organic layer was separated, washed with water (3×40 mL) and dried with sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from toluene at -20° C. to give 1-cyano-1-(4-methoxyphenyl)-2-(4-nitrophenyl)ethylene (yield=0.913 g, 6.5%).
Reaction SMILES: [OH:1][C:2]1[C:11](C(O)=O)=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](C(O)=O)=[N:7]2>N1C2C(=CC=CC=2)C=CC=1>[N:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][N:7]=2)[C:2]([OH:1])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc2c(O)c(C(=O)O)cnc2n1
Solvent: c1ccc2ncccc2c1
Product: Oc1ccnc2ncccc12
Reaction time: 8 h

Procedure:
To quinoline (500 ml) was added 5-hydroxy-1,8-naphthyridine-2,6-dicarboxylic acid (50 g, 340 mmol). The reaction mixture was heated to reflux. After 8 hours, the reaction mixture was cooled and concentrated in vacuo to afford 1,8-naphthyridin-4-ol.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([C:15]1[N:16]([CH2:20][CH:21]([OH:38])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[C:8]([O:12][C:13]([C:15]1[N:16]([CH2:20][C:21](=[O:38])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2cccc2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.14 g (11.2 mmol) acetic anhydride are mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.121 g (0.282 mmol) tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-2-carboxylate in 10 ml absolute DMSO. Having stirred for 16 hours, the batch is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 98:2) and yields the product as a yellowish oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][CH3:22].O.[NH2:31][NH2:32].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:31][N:32]=[C:19]([CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][CH3:22])[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: CCC(C(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(c1ccccc1)c1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-(2-phenylbutyryl)-1,8-naphthyridin-2(1H)-one (98 mg, 0.25 mmol) produced in Synthesis Example 39 in DMF (2 mL) was added hydrazine monohydrate (purity of 80%, 40 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration and washed with water. The precipitate was recrystallized from ethanol and diisopropyl ether to give 5-phenyl-3-(1-phenylpropyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (51 mg, yield 53%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.B.CO>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cccc(C)c1NC(=O)CCCc1cccnc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C)c1NCCCCc1cccnc1

Procedure:
A solution of 13.9 g of N-(2,6-dimethylphenyl)-3-pyridinebutanamide in dry tetrahydrofuran was added dropwise with stirring to an excess of 1 molar borane in tetrahydrofuran and the resulting solution was heated to reflux for two hours. After cooling, excess methanol was added to decompose the remaining borane and the solution was evaporated to dryness. The residue was acidified by the cautious addition of 2N hydrochloric acid and was warmed on the steam bath for 20 minutes. The resulting solution was cooled, made strongly basic with sodium hydroxide solution and was extracted with dichloromethane. The combined layers were dried with potassium carbonate and concentrated to give N-(2,6-dimethylphenyl)-3-pyridine-butanamine as an oil. A solution of the free base in methanol was treated with an excess of fumaric acid in methanol and the resulting solution was diluted with ether. The resulting difumarate was crystallized from 200 ml of 2-propanol to give 20.6 g of N-(2,6-dimethylphenyl) -3-pyridinebutanamine (E)-2-butenedioate(1:2) salt, mp 138°-140° C. (decomposition). Recrystallization from 2-propanol gave the analytical sample, mp 140°-142° C. (decomposition).
Reaction SMILES: [N:1]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)=[N:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:17](OCC)(=[O:19])[CH3:18]>ClCCl>[C:17]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([N:1]=[N:2][C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:8][CH:9]=2)=[CH:11][CH:12]=1)(=[O:19])[CH3:18]
Reactant: CCOC(C)=O
Reactant: Nc1ccc(N=Nc2ccc(N)cc2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N=Nc2ccc(N)cc2)cc1
Yield: 73 %

Procedure:
Following the general monoacylation procedure, 4,4′-azodianiline (25 mg, 120 μmol) was treated with acetyl choloride (8.5 μl, 120 μmol). Silica gel chromatography through a wide column (20% ethyl acetate in dichloromethane, gradient to 66%) provided S1 as an orange solid (22 mg, 90 μmol, 73% yield): 1H (CD3CN, 500 MHz): 1.98 (s, 3H); 4.77 (s, 2H); 6.74 (d, 2H, J=8.5); 7.70 (d, 4H, J=8.5); 7.77 (d, 2H, J=8.5); 8.53 (s, 1H). 13C (CD3CN, 125 MHz): 23.4, 113.9, 119.3, 122.7, 124.7, 140.6, 144.3, 148.6, 151.5, 168.7. HRMS (FAB+): calc'd for C14H14N4O—254.1168, found—254.1171 (M+).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][N:14]3[CH2:18][C:17]4=[CH:19][S:20][CH:21]=[C:16]4[CH2:15]3)[N:10]=[CH:9]2)C=CC=CC=1.[ClH:34]>C(O)C>[ClH:34].[ClH:34].[NH:8]1[CH:12]=[C:11]([CH2:13][N:14]2[CH2:15][C:16]3=[CH:21][S:20][CH:19]=[C:17]3[CH2:18]2)[N:10]=[CH:9]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(CN3Cc4cscc4C3)c2)cc1
Agent: Cl
Solvent: CCO
Product: c1nc(CN2Cc3cscc3C2)c[nH]1
Yield: 86 %

Procedure:
0.14 g (0.3 mmol) of 5-[(1-triphenylmethyl-1H-imidazol-4-yl)methyl]-5,6-dihydro-4H -thieno-[3,4-c]pyrrole is dissolved in 1 ml of ethanol, 1.5 ml of 2M hydrochloric acid is then added and the mixture is heated at reflux for 1 hour. The precipitate formed is filtered and the filtrate is washed with twice 1 ml of ethyl acetate and then evaporated to dryness. The residue is dissolved in 2 ml of methanol and decoloured with active charcoal and then recrystallized from isopropanol. There is obtained 0.075 g of cream-white solid in a yield of 86%. Melting point: 260° C.