Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:33][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCC1
Reactant: CCOC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCOC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 6-chloro-9-(2,3-di-O-acetyl-5-O-ethyl-β-D-ribofuranosyl)-purine (62, 502 mg, 1.26 mmol) and cyclopentylamine (1.89 mmol, 187 μL). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 316 mg (0.87 mmol, 69%), mp 134–136° C.; Rf 0.49 (eluens 10% MeOH in CH2Cl2). The product was re-crystallized from CH3CN; 1H NMR (DMSO-d6) δ 8.31 (s, 1H, H-8), 8.19 (s, 1H, H-2), 7.72 (d, 1H, J=7.55 Hz, NH), 5.89 (d, 1H, J=5.15 Hz, H-1′), 5.55–5.25 (m, 2H, OH-2′,3′), 4.53 (t, 1H, J=4.81 Hz, H-2′), 4.15 (t, 1H, J=2.40 Hz, H-3′), 4.01–3.96 (m, 1H, H-4′), 3.62-3.48 (m, 2H, H-5′), 3.46 (q, 2H, J=7.21 Hz, CH2CH3), 1.99–1.82 (m, 2H, cyclopentyl), 1.78–1.52 (m, 4H, cyclopentyl), 1.11 (t, 3H, J=7.21 Hz, CH3); MS m/z 364 (M+H)+; Anal. (C17H25N5O4.0.6 CH3CN) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([F:25])([F:27])[F:26])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1
Yield: 99.3 %

Procedure:
(R)-3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (559 mg; 3.0 mmol), 4-fluoro-1-nitro-2-trifluoromethyl-benzene (627 mg; 3.0 mmol), potassium carbonate (1.24 g; 9.0 mmol), potassium iodide (498 mg; 3.0 mmol), acetonitrile (6 mL) and water (2 mL) are mixed together and the resulting reaction mixture heated to efflux for 5 hours. The phases are separated and the organic phase dried (MgSO4) and concentrated under high vacuum. The residue is then triturated with diethyl ether, dried under high vacuum to afford the desired compound (1.12 g; 2.98 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:16])[CH3:15]
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1cc([N+](=O)[O-])ccc1C
Reaction time: 0.67 h
Yield: 97.4 %

Procedure:
To a mixture of 2-methyl-5-nitrophenol (2.5 g, 16.3 mmol) and 1M aqueous sodium hydroxide (24.5 ml) was added at ambient temperature acetic anhydride (1.9 ml, 20.3 mmol). The mixture was stirred for 40 minutes, the solid was filtered off and the filtrate extracted with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and evaporated to yield 2-acetoxy-4-nitrotoluene (3.1 g, 100%). A mixture of this material (3.1 g, 15.9 mmol) and 10% palladium-on-charcoal catalyst (0.12 g) in ethyl acetate (50 ml) was stirred at ambient temperature under an atmosphere of hydrogen for 2 hours. The catalyst was filtered off and the filtrate evaporated to give 3-acetoxy-4-methylaniline (2.45 g, 94%).
Reaction SMILES: [CH3:1][C:2]([C:14]1[N:18]([CH3:19])[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])=[N:16][N:15]=1)([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH3:3].S(=O)(=O)(O)O.[CH3:35]O>C(OCC)(=O)C>[CH3:3][C:2]([C:14]1[N:18]([CH3:19])[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:28])([F:29])[F:27])=[N:16][N:15]=1)([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:35])=[O:10])=[CH:7][CH:6]=1)[CH3:1]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)(C)c2nnc(-c3ccccc3C(F)(F)F)n2C)cc1
Temperature: 25 °C

Procedure:
4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (400 mg) was dissolved in methanol (12 ml), concentrated sulfuric acid (0.160 ml) was added thereto, followed by heating to reflux for 2 days. The reaction solution was cooled to room temperature, diluted with ethyl acetate and was washed with a 1M aqueous sodium hydroxide solution, water and saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The resulting solid was washed with diisopropylether to obtain methyl 4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoate (249 mg), as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7]([NH2:9])=[N:6][C:4](=[O:5])[CH:3]=1.[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11].CC(C)=O>CS(C)=O>[CH3:1][C:2]1[NH:8][C:7]([NH:9][C:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:11])=[N:6][C:4](=[O:5])[CH:3]=1
Reactant: Cc1cc(=O)nc(N)[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(=O)nc(NC(=O)n2ccnc2)[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 6-methylisocytosine (1 eq.) and carbonyldiimidazole (1.5 eq.) were combined in dimethylsulfoxide (DMSO) and the solution was stirred at 60° C. for 2 hours. The mixture was cooled to about room temperature and acetone added after which the desired product precipitated as a white powder that was collected by filtration. The procedure of A. T. Cate, P. Y. W. Dankers, H. Kooijman, A. L. Spek, R. P. Sijbesma, and E. W. Meijer, J. of Am. Chem. Soc., 2003, 125, 6860 was followed for this step. The product can be used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:39][NH:38][CH2:37]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C1[C:62]2(OCCC[O:63]2)[CH2:61][C@@H](C(OC)=O)N1C(OCC1C=CC=CC=1)=O>>[C:62]([N:38]1[CH2:37][C:36]2([CH2:40][CH:33]([C:30]3[NH:31][CH:32]=[C:28]([C:25]4[CH:24]=[CH:23][C:22]([C:19]5[CH:20]=[CH:21][C:16]([C:14]6[N:15]=[C:11]([C@@H:7]7[CH2:8][CH2:9][CH2:10][N:6]7[C:4]([C@@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:2]([CH3:57])[CH3:1])=[O:5])[NH:12][CH:13]=6)=[CH:17][CH:18]=5)=[CH:27][CH:26]=4)[N:29]=3)[N:34]([C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:44])[CH3:45])[CH2:35]2)[CH2:39]1)(=[O:63])[CH3:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CNC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCCO2
Product: COC(=O)N[C@H](C(=O)N1CC2(CC1c1nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)c[nH]1)CN(C(C)=O)C2)C(C)C
Yield: 83 %

Procedure:
This compound was prepared in an analogous fashion to Example 21 from methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate Example 24 (40 mg, 0.05 mmol) to afford the title compound as a yellow solid (35 mg, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67-12.33 (m, 1H) 7.19-7.99 (m, 12H) 5.07 (br. s., 1H) 3.92-4.25 (m, 4H) 3.67-3.94 (m, 4H) 3.45-3.66 (m, 8H) 2.20-2.46 (m, 3H) 2.17 (br. s., 2H) 1.80-2.06 (m, 5H) 1.60-1.82 (m, 3H) 0.78-1.02 (m, 12H). HRMS for C44H56N9O7 (M+H)+ calc: 822.4303, found: 822.4300. Purity (LC-MS): 91%.
Reaction SMILES: N1CCCC1.[CH3:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[O:18][C:17]([CH3:20])([CH3:19])[N:16]([C:21](=[O:23])[CH3:22])[C@H:15]2[CH:24]=[O:25])=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:6][S:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[O:18][C:17]([CH3:19])([CH3:20])[N:16]([C:21](=[O:23])[CH3:22])[C@@H:15]2[CH:24]=[O:25])=[CH:12][CH:13]=1
Reactant: CSc1ccc([C@@H]2OC(C)(C)N(C(C)=O)[C@H]2C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CSc1ccc([C@@H]2OC(C)(C)N(C(C)=O)[C@@H]2C=O)cc1

Procedure:
Pyrrolidine (9.6 mg; 0.065 mmol) was added at 25° C. to a solution of compound 4 (see example 3) (100 mg, 0.34 mmol) in toluene (2 ml) kept under magnetic stirring and under nitrogen. At the end of the addition the mixture was kept at 25° C. under stirring for 14 hours. The reaction mixture was then poured into 10% NaHCO3 ; after separation of the phases, the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over sodium sulphate and evaporated to dryness under vacuum.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][OH:9].[CH2:10]=O>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][O:9][CH2:10]1
Reactant: OCCCNCCCO
Reactant: C=O
Solvent: Cc1ccccc1
Product: OCCCN1CCCOC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a glass reaction vessel equipped with stirrer, thermometer, and condenser fitted with a water trap is added di-(3-hydroxypropyl) amine (3.0 mole, 399 g.) and toluene (500 g.). Paraformaldehyde (3.15 mole, 90% pure, 105 g.) is weighed out and about 1/3 is added to the amine solution. The resulting mixture is stirred and heated to 90° C. while slowly adding the remaining paraformaldehyde in about 70 minutes. The reaction is heated to reflux and the water separated. After 4 hours, a total of 63 ml. of water is removed. Toluene is removed at reduced pressure. The residue is distilled at high vacuum to yield 3-(γ-hydroxypropyl)tetrahydro-1,3-oxazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][CH3:16])[C:9]=1[O:10]COC)[CH:5]=[O:6].[C:17]([Cu])#[N:18].CCOC(C)=O>CN(C=O)C>[CH2:15]([O:14][C:8]1[C:9]([OH:10])=[C:2]([CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=1)[C:17]#[N:18])[CH3:16]
Reactant: N#C[Cu]
Reactant: CCOc1cc(C=O)cc(Br)c1OCOC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(C#N)c1O
Temperature: 180 °C
Yield: 49.8 %

Procedure:
A mixture of 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (600 mg, 2.1 mmol) and CuCN (280 mg, 3.1 mmol) in DMF (10 mL) was heated at 180° C. for 4 hours. TLC (PE:EtOAc=1:1) indicated that the most of the starting material was consumed. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the 3-ethoxy-5-formyl-2-hydroxybenzonitrile (200 mg, yield: 50.0%).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[NH2:12][C:11]1[C:2]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-n2ccnc2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.17 g, 10.0 mmol) was dissolved in ethyl acetate (55 mL) and imidazole (4.09 g, 60 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and treated with SnCl2-2H2O (13.5 g, 60.0 mmol). It was heated to 70° C. for 2 h, diluted with potassium carbonate (sat. aq.) and extracted with ethyl acetate (5×20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude yellow solid, which was used in the next step without further purification. [M+H] calc'd for C10H10N4O2, 219; found, 219.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)C=O.N1CCCCC1.[C:31](O)(=O)[CH2:32][C:33]([OH:35])=[O:34].Cl>N1C=CC=CC=1>[Cl:24][C:16]1[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])[CH:12]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 66.7 %

Procedure:
270 g of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-benzaldehyde and 6 g of piperidine were added, at 25° C., to 89.5 g of malonic acid in 570 ml of pyridine. The reaction mixture was stirred for 5 hours at 85° to 90° C. and was then heated for 90 minutes under reflux, after which it was poured onto water, the mixture was acidified with hydrochloric acid and the product was filtered off. The crystalline product was recrystallized from n-butanol. 200 g (66% of theory) of 3-(5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitrophenyl)-propenoic acid, of melting point 192° C., were obtained in the form of yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1F)[C:5]([N:7]1[CH2:10][CH2:9][CH2:8]1)=[O:6].[OH:15][C:16]1[CH:17]=[C:18]([CH:34]=[C:35]([O:37][C@@H:38]([CH3:51])[CH2:39][O:40][Si](C(C)C)(C(C)C)C(C)C)[CH:36]=1)[C:19]([NH:21][C:22]1[CH:26]=[CH:25][N:24](C(OC(C)(C)C)=O)[N:23]=1)=[O:20]>>[N:7]1([C:5]([C:4]2[CH:11]=[CH:12][C:13]([O:15][C:16]3[CH:17]=[C:18]([CH:34]=[C:35]([O:37][C@@H:38]([CH3:51])[CH2:39][OH:40])[CH:36]=3)[C:19]([NH:21][C:22]3[CH:26]=[CH:25][NH:24][N:23]=3)=[O:20])=[C:2]([F:1])[CH:3]=2)=[O:6])[CH2:10][CH2:9][CH2:8]1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1)(C(C)C)C(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)Nc2cc[nH]n2)c1

Procedure:
The synthesis of 1-(3,4-difluorobenzoyl)azetidine is described in Example 8, the synthesis of tert-butyl 3-[(3-hydroxy-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoyl)amino]-1H-pyrazole-1-carboxylate is described below:
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[C:12]=2[F:29])[CH:8]=[CH:9][CH:10]=1>[Fe].O>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=3)[C:12]=2[F:29])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(Cc2ccc([N+](=O)[O-])cc2)c(F)c1-c1cccc(Cl)c1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2ccc(N)cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
In an 18 mL vial equipped with a stir bar was placed iron powder (179 mg, 3.20 mmol), ethanol (5.0 mL) and water (1.2 mL). The mixture was heated to 85° C. in an oil bath and then the above product 3′-Chloro-2-fluoro-6-methoxy-3-(4-nitro-benzyl)-biphenyl (6) (340 mg, 0.914 mmol) was added and the reaction was continued at 85° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite. To the filtrate was added water (50 mL) and extractions were performed with ethyl acetate (2×60 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated to produce 245 mg of 4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine (I-35) as a yellow, viscous oil in 79% yield. MS (APCI+): 342.0 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH:26]4[CH2:27][CH2:28][CH2:29][O:25]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCC1CCCO1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydrofuran-2-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.67 (m, 1H) 1.75-1.89 (m, 2H) 1.89-2.01 (m, 1H) 2.44 (s, 3H) 3.35-3.42 (m, 2H) 3.65 (q, J=7.49 Hz, 1H) 3.80 (q, J=6.82 Hz, 1H) 4.00 (t, J=6.32 Hz, 1H) 7.67 (d, J=7.83 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.18 (br. s., 1H) 8.43 (d, J=6.57 Hz, 2H) 8.82 (t, J=5.31 Hz, 1H) 8.93 (s, 1H) 13.20 (br. s., 1H). MS m/z [M+H]+ 404.2
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.N[CH2:10][C@@H:11]1CC[CH2:13][N:12]1CC.C(=O)C>>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][NH:12][CH3:13])[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: CNCCN1CC[C@H](N(C)C)C1

Procedure:
By using (3S)-(−)-3-(dimethylamino)pyrrolidine (200 mg) as a starting material, the title compound (80 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([F:17])[C:5]2=O.[C:19](=[N:25][Si](C)(C)C)=[N:20][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([F:17])/[C:5]/2=[N:25]\[C:19]#[N:20]
Reactant: O=C1c2cc(Br)ccc2OC2(CCCOC2)C1F
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/c2cc(Br)ccc2OC2(CCCOC2)C1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-3-fluoro-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (220 mg, 0.65 mmol) in anhydrous DCM was added TiCl4 (1 M in DCM, 1.4 mL) dropwise within 15 minutes at room temperature. After addition, the mixture was stirred for 1 h. To this mixture was added N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (264 mg, 1.42 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give crude product, which was used in the next step without further purification.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[C:27]1([OH:30])[CH2:29][CH2:28]1>CC#N>[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12][C:32]([NH:31][C:23]2[CH:24]=[CH:25][C:26]([C:27]3([OH:30])[CH2:28][CH2:29]3)=[C:21]([F:20])[CH:22]=2)=[O:33])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Nc1ccc(C2(O)CC2)c(F)c1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C3(O)CC3)c(F)c2)n(-c2cccc(Cl)c2)n1
Yield: 65.4 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (synthesis described for example A106) (0.104 mg, 0.348 mmol, 1.0 eq) in MeCN (8 mL) was added TEA (0.193 mL, 1.39 mmol, 4.0 eq) followed by addition of phenyl 3-fluoro-4-(1-hydroxycyclopropyl)phenylcarbamate (0.10 mg, 0.355 mmol, 1.02 eq) at RT and the mixture was stirred at reflux overnight. The solvents were evaporated and the crude product was purified by CC (eluent EtOAc/cyclohexane 1:2) to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(1-hydroxycyclopropyl)phenyl)urea (104 mg; 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:75]=[C:74]([O:76][CH3:77])[CH:73]=[C:72]([O:78][CH3:79])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:31]([CH:34](/[CH:58]=[CH:59]/[C:60]1[C:65]([O:66][CH3:67])=[CH:64][C:63]([O:68][CH3:69])=[CH:62][C:61]=1[O:70][CH3:71])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([NH:43][C:44](=[O:57])[C:45]2[CH:50]=[C:49]([N+:51]([O-])=O)[CH:48]=[C:47]([N+:54]([O-])=O)[CH:46]=2)[CH:36]=1)(=[O:33])=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[C:20]([N+:27]([O-])=O)[CH:19]=2)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O.CC(C)=O>[CH3:79][O:78][C:72]1[CH:73]=[C:74]([O:76][CH3:77])[CH:75]=[C:3]([O:2][CH3:1])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:31]([CH:34](/[CH:58]=[CH:59]/[C:60]1[C:61]([O:70][CH3:71])=[CH:62][C:63]([O:68][CH3:69])=[CH:64][C:65]=1[O:66][CH3:67])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([NH:43][C:44](=[O:57])[C:45]2[CH:50]=[C:49]([NH2:51])[CH:48]=[C:47]([NH2:54])[CH:46]=2)[CH:36]=1)(=[O:32])=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:30])[C:18]2[CH:19]=[C:20]([NH2:27])[CH:21]=[C:22]([NH2:24])[CH:23]=2)[CH:9]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc(N)cc(N)c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc(N)cc(N)c3)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4,6-trimethoxystyryl-3-(3,5-dinitrobenzamido)-4-methoxy-benzylsulfone (example 5) (1.3 mmol) in acetone water (10:5) was heated to 50° C. After 30 min, sodiumhydrosulfite (Na2S2O4) (26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C., 1 h.), cooled to room temperature and water was added. The product was rinsed with NaHCO3, and then isolated by extraction with ethyl acetate. The organic layer was dried over-anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was recrystallized from 2-propanol to yield pure (E)-2,4,6-trimethoxystyryl-3-(3,5,diaminobenzamido)-4-methoxy-benzylsulfone. m.p. 208-210° C. NMR (DMSO-d6) δ 3.76 (s, 3H), 3.80 (s, 6H), 3.82 (s, 3H), 4.4 (s, 2H), 5.9 (s, 1H), 6.2 (s, 2H), 7.05-8.26 (m, aromatic), 8.85 (s, 1H).