Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.F[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]>>[CH2:1]([NH:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CO
Product: CCNc1ccccc1[N+](=O)[O-]
Temperature: 55 °C

Procedure:
To a solution of ethylamine in methanol (2.0 M, 150 mL, 300 mmol) was added 1-fluoro-2-nitrobenzene (8 mL, 75.7 mmol). The reaction mixture was placed in a sealed vessel and heated to 55° C. for 15 hours. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (200 mL), washed with a saturated aqueous solution of sodium bicarbonate (80 mL), and dried over anhydrous sodium sulfate (50 g). After removal of solvent, ethyl-(2-nitro-phenyl)-amine (12.5 g, 75 mmol) was obtained as a brown oil. MS (ES) m/z 167.1.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[OH-].[Na+]>CO.C1COCC1>[CH2:24]([N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[C:5]1[C:6]([CH3:11])=[CH:7][C:8]([Br:10])=[CH:9][C:4]=1[C:3]([OH:31])=[O:2])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)cc(Br)cc2C(=O)O)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 0.444 g (0.88 lmmol) of the product of Example 11 in 20 mL of MeOH/THF (1:1) was added 9.3 mL 1N NaOH and the mixture heated at reflux for 18 h. The mixture was cooled to room temperature and the organic removed in vacuo. The remaining solution was acidified with 10% HCl and extracted with EtOAc. The extract was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue provided 0.364 g (84%) of the desired carboxylic acid as a white solid after trturation with ether. CI Mass Spec: 490 (M+H).
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:26]O)=[NH:25])=[CH:22][CH:21]=2)=[N:10]3)[CH2:6][CH2:5]1)([OH:3])=[O:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([C:4]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[NH:25])=[CH:28][CH:29]=2)=[N:10]3)[CH2:6][CH2:5]1)([OH:3])=[O:2]
Reactant: Cn1c(=O)c(Cc2ccc(C(=N)NO)cc2)nc2cc(C3(C(=O)O)CC3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1c(=O)c(Cc2ccc(C(=N)N)cc2)nc2cc(C3(C(=O)O)CC3)ccc21

Procedure:
300 mg (0.76 mmol) of 4-{[6-(1-carboxy-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N-hydroxybenzamidine are dissolved in 30 ml of 90% acetic acid and after the addition of 400 mg palladium on activated charcoal hydrogenated with hydrogen at 60° C. The catalyst is filtered off, the solution is evaporated down. The residue is chromatographed on silica gel and eluted with methanol. The desired fractions are evaporated down, triturated with ether, suction filtered and dried.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:17]>>[CH3:17][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Product: Cc1cccc([N+](=O)[O-])c1N1CCNCC1

Procedure:
1-(2-Methyl-6-nitrophenyl]piperazine was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 2-bromo-1-methyl-3-nitro-benzene. LRMS (ESI+): 222.4 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:20][CH2:21][CH2:22][O:23][C:24]1[C:31]([CH3:32])=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[CH3:33]>C(O)C.[Cu](Cl)Cl>[OH:20][CH2:21][CH2:22][O:23][C:24]1[C:31]([CH3:32])=[CH:30][C:27]([C:28]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:1]=2)=[CH:26][C:25]=1[CH3:33]
Reactant: CC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cl[Cu]Cl
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(C(C)C)cc2)cc(C)c1OCCO

Procedure:
To a solution of 2-amino-N-(4-isopropylphenyl)benzamide (0.400 g, 1.57 mmol) and 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.30 g, 1.57 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.63 g, 4.71 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with dichloromethane (150 mL) and water (100 mL). The organic phase was separated and further washed with water (100 mL), brine (100 mL), and dried over sodium sulfate. The crude mixture was purified by column chromatography on silica gel (230-400 mesh) using hexane/ethyl acetate (1:1) as eluent to give the title compound as a white solid. Yield: 100 mg (15.6%). MP 160-162° C. 1H-NMR (400 Hz, CDCl3): δ 8.34 (d, J=7.6 Hz, 1H), 7.80 (m, 2H), 7.52 (m, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.97 (s, 2H), 3.90 (m, 2H), 3.78 (t, J=4.8 Hz, 2H), 2.86 (m, 1H), 2.13 (s, 6H), 2.06 (t, J=6.4 Hz, 1H), 1.20 (d, J=7.2 Hz, 3H). MS (ES+) m/z: 429.52 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12]C)=O)[CH2:4][CH2:3]1.[CH2:14]([NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)(Cl)Cl.CO>[CH2:14]([NH:26][C:10](=[O:12])[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)CCN1CCN(C)CC1
Reactant: CCCCCCCCCCCCN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)CCN1CCN(C)CC1
Temperature: 185 °C

Procedure:
Methyl 3-(4-methylpiperazin-1-yl)propanoate 40.0 g (0.21 moles) and dodecylamine 39.7 g (0.21 moles) are charged into a 3-neck 250-mL round bottom flask equipped with a Dean-Stark trap, thermocouple, and reflux condenser. The mixture is agitated using a magnetic stirring bar and heated to 185° C. for five hours. The volume of methanol that is distilled from the reaction is used to monitor the progress of the reaction. Evidence of the chemical transformation is observed by thin layer chromatography (TLC) analysis using a 4:1 CHCl3/MeOH as mobile phase. The final product is a light yellow solid at ambient temperature. 1H-NMR (300 MHz, CDCl3): δ 2.98 (m, 2H), 2.07 (m, 15H), 1.27 (m, 2H), 1.0 (m, 18H), 0.65 (t, 6.7 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ 171.70, 54.60, 54.39, 54.34, 53.45, 51.86, 45.39, 38.45, 31.60, 31.38, 29.14, 29.11, 28.93, 28.85, 28.83, 26.65, 22.15, 13.61.
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[CH:35](=O)[C:36]1[O:40][CH:39]=[CH:38][CH:37]=1.[BH3-]C#N.[Na+]>CO>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:35][C:36]2[O:40][CH:39]=[CH:38][CH:37]=2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=Cc1ccco1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3ccco3)C3CCCc4cccnc43)cc2)nc1
Yield: 52.3 %

Procedure:
To a stirred solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.206 g, 0.449 mmol) in anhydrous methanol (10 mL), at room temperature, was added furfural (0.19 mL, 2.29 mmol) followed by NaBH3CN (0.070 g, 1.11 mmol) and the resultant solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and CH2Cl2 (20 mL) and 1.0 M aqueous NaOH (10 mL) were added to the residue. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography silica gel (25:1 CH2Cl2-MeOH) provided 0.103 g of the protected amine as a yellow oil.
Reaction SMILES: [C:1](/[CH:3]=[C:4](/[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)\SC)#[N:2].O.[NH2:21][NH2:22]>CCO>[NH2:2][C:1]1[NH:22][N:21]=[C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:3]=1
Reactant: NN
Reactant: CS/C(=C\C#N)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)[nH]n2)CC1
Temperature: 25 °C

Procedure:
A mixture of (Z)-tert-butyl 4-(2-cyano-1-(methylthio)vinyl)piperazine-1-carboxylate (5.94 g, 20.9 mmol) and hydrazine monohydrate (4.5 mL) in EtOH (50 mL) was heated to reflux for 14 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography, eluting with 0-10% MeOH/CH2Cl2 to give tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@H:10]2[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([NH:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@H:10]2[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(OC[C@@H]2CO2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(OC[C@@H]2CO2)c1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
Compound 16b-S (0.4 g, 2.4 mmol) dissolved in 20 ml anhydrous DCM, and N,N-diisopropyl-N-ethylamine (0.45 ml, 2.6 mmol) was added at 0° C. After stirring for 15 minutes, methanesulfonyl chloride (0.2 ml, 2.6 mmol) was added to the reaction mixture at 0° C. After stirring overnight, the reaction mixture was extracted with water and washed with brine. The organic phase was dried and evaporated. The residue was purified with flash chromatography using ethyl acetate:DCM (30:70) solvent to give a colorless oil (45% yield).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:21])=[CH:18][C:19]=1[OH:20])=[O:13].C([O:24][C:25](=O)[C:26]1[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[C:28]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:27]=1)C.Cl>O1CCCC1>[CH2:41]([O:40][C:28]1[CH:27]=[C:26]([C:25](=[O:24])[CH2:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:21])=[CH:18][C:19]=2[OH:20])=[O:13])[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(O)cc1O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (217.5 mL, 260 mmol) was added to a well-stirred solution of 2,4-dihydroxy acetophenone, 14 (9.88 g, 65 mmol) in tetrahydrofuran (150 mL) under nitrogen atmosphere at −78° C. for 30 min. The reaction mixture was stirred at −78° C. for 1 h and at −30° C. for 2 h. It was again cooled to −78° C. and a solution of ethyl-3,5-dibenzyloxy-benzoate 8 (23.5 g, 65 mmol) in tetrahydrofuran (100 mL) was added over a period of 30 min. It was further stirred at room temperature for overnight and poured into ice water containing hydrochloric acid. It was extracted with chloroform, dried over sodium sulphate, filtered and evaporated on rotavapor to afford 1-(3,5-bis-benzyloxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (16). The residue, 16 (37.8 g) was refluxed with Dowex-H+ (8 g) in 2-propanol (300 mL) for 3-4 h. 2-Propanol was evaporated on rotavapor, residue suspended in hot dimethyl formamide and filtered. The filtrate was concentrated under reduced pressure and the product was washed with cooled methanol (3*200 mL) to afford 22. Yield 23.8 g (81%); mp 248-249° C.; MS (FAB) 451 (M++1); IR (KBr) 3452, 1620; 1H NMR (200 MHz, DMSO-d6) δ 7.84 (d, J=8.7 Hz, 1H), 7.52-7.28 (m, 10H), 7.23 (d, J=1.9 Hz, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.89 (s, 1H), 6.89 (dd, J=8.6 Hz, 2.1 Hz, 1H), 6.82 (s, 1H), 5.14 (s, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl>[CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([N:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:42](=[O:44])[CH3:43])[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOc1cc(F)c(Cn2nc(-c3nccc(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(F)c(Cn2nc(-c3nccc(N(C(C)=O)c4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)-pyrimidin-4-amine (5-1-1, 0.218 mmol, 1. eq.) was dissolved in 2 ml of dry dichloromethane. First 94 μl of dry N,N-diethylethanamine (0.676 mmol, 3.1 eq.) and then 23 μl of acetyl chloride (0.327 mmol, 1.5 eq,) were added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours. Then the mixture was partitioned between water and dichloromethane. The phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 29.8 mg (0.06 mmol, 26.8%) of the analytically pure target compound.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([C:25](=[CH:26]O)[C:24](=O)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH:34][NH2:35]>C(O)C>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([C:25]4[C:24](=[N:35][N:34]([CH3:33])[CH:26]=4)[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2C(=O)C3=CO)ccc1C(C)(C)C
Reactant: CNN
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2nn(C)cc23)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
A mixture of 1′-(4-tert-butyl-3-methoxy-benzoyl)-3-(hydroxymethylene)-spiro[chromane-2,4′-piperidine]-4-one (50 mg, 0.12 mmol) and methylhydrazine (6.7 μL, 0.13 mmol) in ethanol (1.6 mL) was allowed to stir at 25° C. for 3 h. The mixture was filtered and then purified by reverse phase HPLC to provide (4-tert-butyl-3-methoxy-phenyl)-(2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (8 mg, 15%) (peak 1) and (4-tert-butyl-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (peak 2). (4-tert-Butyl-3-methoxy-phenyl)-(2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone: ESI-MS m/z calc. 445.2. found 446.3 (M+1)+; Retention time: 1.87 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.2-7.20 (m, 1H), 7.17-7.10 (m, 1H), 7.06-6.94 (m, 2H), 6.93-6.83 (m, 2H), 4.25-4.05 (m, 1H), 4.02-3.93 (m, 1H), 3.85-3.75 (m, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.55-3.40 (m, 1H), 2.37-2.18 (m, 2H), 1.35 (s, 9H), 1.30-1.15 (m, 2H). (4-tert-Butyl-3-methoxy-phenyl)-(1-methylspiro-[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone: ESI-MS m/z calc. 445.2. found 446.3 (M+1)+; Retention time: 2.10 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=7.5 Hz, 1H), 7.32-7.25 (m, 2H), 7.18 (t, J=7.7 Hz, 1H), 7.08-6.88 (m, 3H), 6.84 (t, J=7.5 Hz, 1H), 4.43-4.32 (m, 1H), 4.20-4.05 (m, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.76-3.55 (m, 2H), 2.26-2.25 (m, 2H), 1.80-1.50 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:17])[NH:5][C:6]2[CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH:12]=1)#[N:2].[OH-:18].[Na+]>S(=O)(=O)(O)O>[CH:12]1[C:11]2[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:17])[C:3]=1[C:1]([NH2:2])=[O:18]
Reactant: [OH-]
Reactant: N#Cc1cc2c([nH]c1=O)CCc1ccccc1-2
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1cc2c([nH]c1=O)CCc1ccccc1-2
Temperature: 0 °C

Procedure:
Heat 5.5 gm 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)one in 50 ml of 90% sulfuric acid at 100° for 11/2 hours. Cool the reaction mixture, pour into ice water and basify the aqueous mixture with 50% sodium hydroxide to give a tan precipitate. Filter the mixture and recrystallize the solid (dimethylformamide:acetonitrile) to give the title compound.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH3:10])[C:5]=1[CH:11]=[O:12]>CO>[Cl:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][OH:12]
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nn(C)c(Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium borohydride (358 mg, 9.5 mmol) in methanol (15 mL) was added a solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (1.0 g, 6.3 mmol) in methanol (5 mL) at 0° C. The mixture was stirred overnight at room temperature. The solvent was evaporated, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methanol was obtained as a white solid (690 mg, 68% yield) and used in the next step without further purification; 1H NMR (400 MHz, CDCl3): δ 1.53 (t, J=5.5 Hz, 1H), 2.28 (s, 3H), 3.77 (s, 3H), 4.49 (d, J=5.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Yield: 53.5 %

Procedure:
(R)-3-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (55 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (45 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].Cl[S:8]([C:11]1[C:12]([F:21])=[C:13]([C:17]([F:20])=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9].S(=O)(=O)(O)O>O>[F:21][C:12]1[C:11]([S:8]([OH:10])=[O:9])=[CH:19][CH:18]=[C:17]([F:20])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)ccc(S(=O)(=O)Cl)c1F
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(F)ccc(S(=O)O)c1F
Reaction time: 0.33 h

Procedure:
240 mmol of sodium sulfite were dissolved in 150 ml of water. 32 mmol of 3-Chlorosulfonyl-2,6-difluoro-benzoic acid was added under stirring over a period of about 20 min. After stirring for an additional hour at room temperature, the mixture was chilled and acidified with 20% aqueous sulfuric acid. The product was extracted with ethyl acetate to yield the title compound as a colorless solid. MS (m/e): 221.3 (M−H, 34%)
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:27])[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[CH2:14][C:13]([CH3:26])([CH3:25])[NH:12]1>C1(C)C(C)=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[C:13]([CH3:25])([CH3:26])[CH2:14][CH:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[CH2:16][C:11]2([CH3:27])[CH3:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(=O)CCCCNC1CC(C)(C)NC(C)(C)C1
Solvent: Cc1ccccc1C
Product: CC(=O)CCCCNC1CC(C)(C)N(c2nc(Cl)nc(Cl)n2)C(C)(C)C1

Procedure:
9.2 g of cyanuric chloride and 26.7 g of 2,2,6,6-tetramethyl-4-(N-acetylbutylamino)-piperidine are reacted in 100 ml of xylene as described in Example 1 and worked up. 2,4-Dichloro-6-[2,2,6,6-tetramethyl-4-(N-acetylbutylamino)-piperidin-1-yl)-1,3,5-triazine is obtained as colorless crystals having a melting point of 131°-133°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][C@@H:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Product: CC(=O)c1ccc(Nc2ccc(C[C@H](C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(4-chloro-3-nitrophenyl)ethanone and (2S)-1-(4-aminophenyl)-2-propanol (step 2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]([CH3:17])[C:7]([C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:8][N:9]=1)(=[O:4])=[O:3].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=O)([O-])[O-].[Ag+].[Ag+]>[CH2:18]([O:16][C:12]1[CH:11]=[C:10]([C:7]2[N:6]([CH3:17])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:9][N:8]=2)[CH:15]=[CH:14][N:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(-c2cc[nH]c(=O)c2)nnc1S(C)(=O)=O
Agent: [Ag+]
Agent: O=C([O-])[O-]
Product: Cn1c(-c2ccnc(OCc3ccccc3)c2)nnc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound from example 27.1 (0.95 g, 3.7 mmol) and silver (1) carbonate (1.23 g, 4.48 mmol) were combined in a round bottom flask and purged with nitrogen. Toluene (10 mL) was added, followed by benzyl bromide (0.53 mL, 4.48 mmol) and the reaction was stirred for 72 h at room temperature. The silver salts were then removed by filtration through diatomaceous earth, which were then washed with dichloromethane. The filtrate was concentrated then purified by column chromatography on silica gel with 0-10% ethyl acetate in dichloromethane to give the title compound (off-white solid, 549 mg, 43