Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.[CH2:25]=O.[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[N:8]([CH3:25])[CH2:7][CH2:6]2
Reactant: C=O
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(O)c32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3O)CCN2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
6,7-Dimethoxy-1-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-8-ol (2.55 g, 7.74 mmol) obtained in Example 1-2 was dissolved in 100 ml of chloroform-methanol (1:1), 35% formalin (3.6 ml, 45.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. Sodium borohydride (3.40 g, 89.8 mmol) was added under ice cooling and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, 200 ml of water was added to the resultantresidue, and the mixture was neutralized with 1N hydrochloric acid and thenextracted with chloroform (100 ml×3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to give 2.09 g (yield: 79%) of the captioned compound as pale yellow powder. Melting point: 112°-114° C. FAB-MS (m/z, (C20H25NO4 +H)+ ): 344 1H-NMR (300MHz, CDCl3, δ ppm): 2.35 (3H, s), 2.35-2.45 (1H, m), 2.73-2.87 (2H, m), 2.98 (1H, dd, J=3.2Hz, 14.2Hz), 3.20-3.32 (1H, m), 3.78(3H, s), 3.83 (3H, s), 3.88 (3H, s), 3.95 (1H, d, J=3.2Hz, 8.8Hz), 6.20 (1H, s), 6.80 (1H, d, J=8.8Hz), 7.18 (1H, d, J=8.8Hz)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[C:26]1([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[ClH:1].[ClH:1].[CH2:22]([CH:21]([N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:35]4[CH2:34][CH:33]=[C:32]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:37][CH2:36]4)=[CH:4][CH:5]=3)[O:13][N:12]=2)[CH2:16][CH2:17]1)[CH2:24][CH3:25])[CH3:23]
Reactant: CCC(CC)N1CCC(Cc2noc(-c3ccc(CCl)cc3)n2)CC1
Reactant: C1=C(c2ccccc2)CCNC1
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc(CN4CC=C(c5ccccc5)CC4)cc3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 23, starting from 4-[5-(4-(chloromethyl)phenyl)[1,2,4]oxadiazol-3-ylmethyl]-1-(1-ethylpropyl)piperidine and 4-phenyl-1,2,3,6-tetrahydropyridine. HPLC: Rt=10.24 min.
Reaction SMILES: [Na].[C:2]1(=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.I[CH2:16][CH2:17][CH3:18]>CO>[CH2:16]([S:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][C:2]2=[O:14])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[CH2:17][CH3:18]
Reactant: O=C1CCc2ccc(S(=O)O)cc21
Reactant: CCCI
Agent: [Na]
Solvent: CO
Product: CCCS(=O)(=O)c1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.25 g of sodium is dissolved in 50 ml of anhydrous methanol. 1.96 g of indan-1-one-6-sulfinic acid (see above) are added in portions and the mixture is stirred for 30 min at room temp. 1.87 g of 1-iodopropane are then added and the mixture is stirred for 4 hours at reflux temp. For completion of the reaction, the mixture is concentrated in vacuo, treated with 5 ml of iodopropane and 10 ml of toluene and heated to reflux for 2 hours. It is then concentrated, the residue is extracted by shaking with water and CH2Cl2, the org. phase is dried and concentrated, and the residue is purified by column filtration (SiO2 ; cyclohexane/ethyl acetate=2/1). 6-(Propane-1-sulfonyl)indan-1-one of melting point 100° C. is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:22]#[N:23])([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:11]1([C:22]#[N:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2Cl)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To 4-cyano-4-(2,4-dichlorophenyl)piperidine-1-carboxylic acid tert-butyl ester (0.620 g, 1.74 mmol) in 5 ml of dichloromethane, 2 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.442 g (99%) of 4-(2,4-dichlorophenyl)piperidine-4-carbonitrile which was used as such for the subsequent step.
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@@H:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][O:8][C@H:9]2[C@@H:14]([NH:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(N[C@H]1CCN(Cc2ccccc2)C[C@H]1OCc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H]1CCNC[C@H]1OCc1ccccc1)c1ccccc1

Procedure:
A mixture of 150 parts of cis-N-[3-(phenylmethoxy)-1-(phenylmethyl)-4-piperidinyl]benzamide and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 9 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a first fraction of 42 parts of cis-N-[3-(phenylmethoxy)-4-piperidinyl]-benzamide.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])(=O)C.[K+].C(O)CCC>CCOCC.O>[F:10][C:11]1[C:16]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1cccnc1F
Reactant: CNc1cc(Cl)ncn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCO
Product: CNc1cc(-c2cccnc2F)ncn1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To an RBF, under a reflux condenser, was added 6-chloro-N-methylpyrimidin-4-amine (5.0 g, 35 mmol), 2-fluoropyridin-3-ylboronic acid (7.4 g, 52 mmol), potassium acetate (10 g, 104 mmol), 1-butanol (100 mL) and DI water (20 mL). The mixture was purged with Ar (vacuum/purge three times to remove oxygen), then PdCl2(P-t-Bu2Ph)2 (0.26 g, 0.42 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 17 h. The reaction mixture was allowed to cool to room temperature and diluted with Et2O (500 mL). The mixture was washed with water (3×200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to ˜100 mL bright yellow butanol solution. The solution was azeotroped with hexane (3×500 mL). Upon the third azeotrope (volume ˜90 mL) a white precipitate was observed. The suspended solid was collected by solution filtration and vacuum-dried to afford 2.48 g as a white solid. The filtrate was diluted with Et2O (300 mL) and extracted with 1 N aq HCl (2×150 mL). The aqueous extract was basified with 5 N NaOH and extracted with Et2O (2×150 mL). The organic extract was washed with saturated NaCl (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 2.48 g as an off-white solid. Total yield of title compound: 6-(2-fluoropyridin-3-yl)-N-methylpyrimidin-4-amine (4.95 g, 70%). MS (M+H)+ 205.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[CH:26]1[CH2:31][CH2:30][CH2:29][N:28]2[N:32]=[C:33]([NH2:35])[N:34]=[C:27]12>>[F:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[CH:26]1[CH2:31][CH2:30][CH2:29][N:28]2[N:32]=[C:33]([NH:35][CH:11]3[CH2:12][CH2:13][N:8]([C:4]4[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=4)[CH2:9][CH2:10]3)[N:34]=[C:27]12
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: Nc1nc2n(n1)CCCC2c1ccc(C(F)(F)F)cc1F
Product: Cc1cc(N2CCC(Nc3nc4n(n3)CCCC4c3ccc(C(F)(F)F)cc3F)CC2)ncn1

Procedure:
Prepared in analogy to example 1h employing 1-(6-methylpyrimidin-4-yl)piperidin-4-one and 8-(2-fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 1d-g). The title compound was obtained as light yellow foam. MS ISP (m/e): 476.2 (100) [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([NH:5][CH2:6][C@@H:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:13](N=N[N:17]=3)[CH:14]=2)[OH:8])[CH2:4][CH2:3]1.[Cl:18][Sn]Cl>CO.Cl>[ClH:18].[ClH:18].[NH2:17][C:12]1[N:13]=[CH:14][C:9]([C@H:7]([CH2:6][NH:5][C:2]2([CH3:1])[CH2:4][CH2:3]2)[OH:8])=[CH:10][CH:11]=1
Reactant: Cl[Sn]Cl
Reactant: CC1(NC[C@H](O)c2ccc3nnnn3c2)CC1
Agent: Cl
Solvent: CO
Product: CC1(NC[C@H](O)c2ccc(N)nc2)CC1
Yield: 30.2 %

Procedure:
To a solution of 319 mg (1.37 mmol) of (R)-α-[[(1-methylcyclopropyl)amino]methyl]tetrazolo [1,5-a]pyridine-6-methanol in 25 ml of methanol, 0.12 ml of 12 N HCl and 622 mg (2.75 mmol) of SnCl2 ·2H2O were added. This mixture was heated at reflux for 8 hours and then concentrated to dryness. The residue was partitioned between 80:20 methylene chloride:methanol and 5 ml of 2.5 N NaOH solution. The layers were separated and the aqueous layer repeatedly extracted with 80:20 methylene chloride:methanol. The combined extracts were dried with anhydrous magnesium sulfate and concentrated under reduced pressure, wt. 355 mg. Purification was accomplished by preparative Tlc on silica gel (90:10:1 methylene chloride:methanol:conc. ammonium hydroxide) to give 116 mg of product which was converted into its hydrochloride salt in ethanolic HCl. The salt was precipitated with ether, 105 mg; [α]25D=-28.5 (MeOH, c=1.5); Analysis: Calcd. for C11H17N3O·2HCl:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:17])([CH3:16])[CH3:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH3:20]I.O>C1COCC1>[CH3:20][O:17][C:14]([C@H:11]1[CH2:12][CH2:13][C@H:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:9][CH2:10]1)([CH3:15])[CH3:16]
Reactant: CC(C)(O)[C@H]1CC[C@H](OC2CCCCO2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(C)[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((trans)-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl)propan-2-ol (1.56 g, 6.5 mmol) in THF (10 mL) was added NaH (300 mg, 13 mmol, 2.0 eq) slowly at r.t. and then CH3I (1.96 g, 13 mmol, 2.0 eq) was added in one portion. The mixture was stirred at 50° C. for 2 h, Water (10 mL) was added and the mixture was extracted with EA (30 mL×3), dried and concentrated to give the title compound as a colorless oil (1.2 g, yield: 72%). 1H NMR (400 MHz, CDCl3) δ: 4.64 (t, 1H), 3.93-3.89 (m, 2H), 3.51-3.47 (m, 1H), 3.17 (s, 3H), 1.97-1.85 (m, 3H), 1.70-1.67 (m, 1H), 1.58-1.43 (m, 9H), 1.34-1.27 (m, 2H), 1.09 (d, 6H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.CN([CH:21]=[O:22])C>>[Cl:3][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:21]=[O:22]
Reactant: OCCc1ccc2[nH]ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: O=Cc1c[nH]c2ccc(CCCl)cc12
Temperature: 80 °C
Yield: 90 %

Procedure:
A solution of 1.46 mL (15.7 mmol) phosphorous oxychloride in 5 mL DMF is stirred for 20 minutes. A solution of 2.11 g (13.1 mmol) 5-(2-hydroxyethyl)indole (reference example 6) in 5 mL DMF is added, and the reaction mixture is heated to 80° C. for ten minutes. The reaction is quenched with solid sodium bicarbonate and diluted with 250 mL 1:1 CH2Cl2:MeOH. The inorganic solids are filtered off, and the filtrate concentrated. The resulting residue is refluxed in 75 mL 1N HCl solution for one hour, then extracted with CH2Cl2. The organic extracts are combined and concentrated, and the residue chromatographed (20:1 CH2Cl2:MeOH) to provide 2.45 g of the product as a brown solid in 90% yield. 1H NMR (CDCl3): δ 3.19 (2H, t, J=7 Hz), 3.76 (2H, t, J=7 Hz), 7.20 (1H, dd, J=8, 1 Hz), 7.40 (1H, d, J=8 Hz), 7.85 (1H, d, J=3 Hz), 8.19 (1H, s), 8.98 (1H, br), 10.05 (1H, s). MS (EI) m/z 207, 209 (M[35Cl, 37Cl])+, 158 (M−CH2Cl)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:17][S:18]([NH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:20])=[O:19].C(N(CC)CC)C>C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][NH:21][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:29][CH2:28]1
Reactant: CS(=O)(=O)NCCC1CCNCC1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2ncnc(N3CCC(CCNS(C)(=O)=O)CC3)c2cc1OC
Temperature: 25 °C
Yield: 88 %

Procedure:
4-Chloro-6,7-dimethoxy quinazoline (1.1 g.), 4- (2-methanesulphonamidoethyl)piperidine hydrochloride (1.5 g.) and triethylamine (1.5 ml.) in ethanol (30 ml.) were heated together under reflux for 1.5 hours. The solution was then cooled to room temperature, concentrated in vacuo, suspended in water (70 ml.) and basified to pH 10 with 10% aqueous sodium carbonate solution. The mixture was extracted with chloroform (2×70 ml.), the extracts combined, dried (MgSO4), and taken to dryness in vacuo. The resultant pale yellow oil was triturated with ether (70 ml.) to give a white solid which was collected by filtration. Crystallization of this solid from ethanol yielded 6,7-dimethoxy-4-[4-(2-methanesulphonamidoethyl)-piperidino]quinazoline (1.7 g.), m.p. 162°-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:31]1([CH:36]2[CH2:41][CH2:40]NC[CH2:37]2)[CH:35]=[CH:34][CH:33]=[N:32]1.C1C=[N:46][C:45]2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:20][C@H:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C@H:12]1[CH2:11][CH2:10][C@@H:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:46]3[CH2:37][CH:36]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)[CH2:41][CH2:40][CH2:45]3)=[O:27])=[CH:29][CH:30]=2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: c1cnn(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1cccnc1
Reactant: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCCC(n4cccn4)C3)cc2)CC[C@@H]1[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 4-{((2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(pyridin-3-yl)methyl]pyrrolidin-2-yl)methyl}benzoic acid (i-4, 40 mg, 0.1 mmol) and 4-(1H-pyrazol-1-yl)piperidine (15 mg, 0.1 mmol) in 1.0 mL anhydrous DMF was added a 0.5 M solution of HOAt in DMF (0.2 mL, 0.1 mmol) followed by EDC (40 mg, 0.2 mmol) and DIEA (35 μL, 0.2 mmol). The resulting mixture was stirred at RT under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×5 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate (1000 uM) eluting with 10% MeOH in dichloromethane to afford the title compound (38 mg, 75%). ESI-MS calculated for C31H39N5O4: Exact Mass: 545.30. Found 546.30 (MH)+ and 568.28 (MNa)+.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:24])[CH2:7][N:8]([CH:21]1[CH2:23][CH2:22]1)[S:9]([C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=1[Cl:20])(=[O:11])=[O:10])C>O.C1COCC1>[CH:21]1([N:8]([CH2:7][C:6]([OH:24])=[O:5])[S:9]([C:12]2[C:13]([Cl:20])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[Cl:18])(=[O:11])=[O:10])[CH2:22][CH2:23]1
Reactant: CCOC(=O)CN(C1CC1)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN(C1CC1)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl

Procedure:
A soln. of lithium hydroxide (298 mg, 12.5 mmol) in water (15 ml) was added to a soln. of [cyclopropyl-(2,4,6-trichlorobenzenesulfonyl)-amino]-acetic acid ethyl ester (2.91 g, 7.5 mmol) in THF (25 ml) and the mixture was stirred at RT for approx. 18 h. The mixture was concentrated i. vac. and water was added to the residue. The alkaline residue was extracted with MC (2×50 ml). The aqueous phase was adjusted to pH 1-2 with conc. hydrochloric acid and extracted with EtOAc (3×30 ml). These combined organic phases were dried with Na2SO4 and concentrated i. vac. Toluene was repeatedly added to the residue and the mixture concentrated i. vac. Yield: 1.77 g (65%)
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[C:10](Br)[C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.C(O)=O.C(N(CC)CC)C>[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(Br)cnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 78 %

Procedure:
Toluene (30 ml) was added to 2.0 g (4.5 mmol) of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine, 1.24 g (27.0 mmol) of formic acid, 4.55 g (45.0 mmol) of triethylamine and 10% Pd-C (100 mg), followed by heating under reflux for 6 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (50 ml) and water (50 ml) were added to the residue and the obtained mixture was caused liquid--liquid separation. The aqueous phase was further extracted with chloroform (30 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.28 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 78%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:19]1([O:25][C:26]([N:5]2[C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=[C:4]2[C:8]([F:11])([F:10])[F:9])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: FC(F)(F)c1nc(Cl)c(Cl)[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Oc1ccccc1)n1c(C(F)(F)F)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
20.5 g (0.1 mol) of 4,5-dichloro-2-trifluoromethylimidazole were dissolved in 150 ml of dioxane. 10.1 g (0.1 mol) of triethylamine were added thereto and 16.05 g (0.1 mol) of chloroformic acid phenyl ester were then added dropwise whilst cooling at 10°-15° C. The mixture was stirred for a further 2 hours at room temperature, the triethylamine hydrochloride which had separated out was filtered off and the filtrate was evaporated in vacuo. The oily residue was distilled. The main fraction boiled at 106.5°-107° C./0.08 mm Hg. 28.6 g (88% of theory) of 4,5-dichloro-2-trifluoromethyl-imidazole-1-carboxylic acid phenyl ester were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:27](=O)([O-])[NH2:28].C[N:32]([CH:34]=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:32][CH:34]1[CH2:6][CH2:5][CH:4]([CH2:27][NH:28][C:2]2[CH:3]=[CH:4][C:5]([C:17]([F:20])([F:19])[F:18])=[C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][N:9]=3)[N:7]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)[O-]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc(Cl)nc1-c1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(CNc2ccc(C(F)(F)F)c(-c3n[nH]c4ncccc34)n2)CC1
Temperature: 115 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
A mixture of 3-(6-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.33 mmol), K2CO3 (55.53 mg, 0.40 mmol) and tert-butyl N-[4-aminomethyl)cyclohexyl]carbamate (86.11 mg, 0.40 mmol) in DMF (1 mL) were heated at 115° C. for 8 hours. The reaction was worked up by diluting with DCM, washing with saturated aqueous bicarbonate and brine. After drying over MgSO4, the mixture was filtered and evaporated to dryness to give an orange residue. The residue was taken up in TFA/DCM (1 ml/3 ml) and stirred at RT for 2 hours. Reaction mixture was concentrated and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (29 mg, 17% Yield).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[S:5](=[O:9])(=[O:8])([OH:7])[OH:6]>O>[NH2:1][C:2]([NH2:4])=[O:3].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[NH4+:1].[NH4+:1]
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Solvent: O
Product: O=S(=O)([O-])[O-]
Product: [NH4+]

Procedure:
Similar tests were made in which low pH N-S solution type fertilizers were produced by mixing commercial nitrogen solution (35 percent CO(NH2)2, 45 percent HN4NO3, and 20 percent H2O) with urea and sulfuric acid. When only the nitrogen solution was mixed with sulfuric acid and water to produce a 25 percent N and 4 percent S grade, a large amount of urea and ammonium sulfate crystals formed in the fluid and it solidified. When urea was substituted for part of the nitrogen solution, less crystallization was observed in the fluid products. When the CO(NH2)2, N:NH4NO3, N mole ratio was increased to 11.3, a clear solution resulted which remained free of crystals for several weeks at room temperature. A grade which contained 25 percent N and 4 percent S with a CO(NH2)2, N:NH4NO3, N mole ratio of 12.0 had a salt-out temperature of 45° F. This solution was mixed with the 8- 24-0 described earlier to produce N-P-S grades. The pH of the product was 1.7. This 25-0-0-4S was also used with phosphoric acid and potash (KCl) to produce mixtures that contain potassium such as an 8-8-8-1.3S. This mixture has a salting-out temperature of -8° F.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16]
Reactant: NOCc1ccccc1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Agent: Cl
Product: CNc1ccccc1C(=O)NOCc1ccccc1
Yield: 29.3 %

Procedure:
In the same manner as Example 35(a), O-benzylhydroxylamine hydrochloride (1.92 g, 12 mmol) reacted with N-methylisatoic anhydride (2.0 g, 10 mmol) to give 2-methylamino-N-benzyloxylbenzamide as a yellow solid (0.75 g).