Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[C:4]2[CH:9]=[C:10]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC#Cc1cc(F)cnc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cc2cc(F)cnc2[nH]1
Temperature: 25 °C

Procedure:
5-Fluoro-3-prop-1-ynyl-pyridin-2-ylamine (14.0 g, 90.0 mmol) was treated with a 1M solution of potassium tert-butoxide in tert-butanol (150 mL) and the reaction mixture was heated at 85 OC for 1 hour. The mixture was then allowed to cool to ambient temperature and poured onto a 1:1 mixture of water/ice (ca. 1 L). The resultant precipitate was collected by filtration, washed with water and left to air dry. The resultant solid was dissolved in dichloromethane, dried (Na2SO4), filtered and evaporated then triturated with diethyl ether to afford the title compound as a buff solid (9.2 g, 66%). 1H NMR (300 MHz, CDCl3): 10.61 (s, 1H), 8.12 (s, 1H), 7.51 (dd, J=9.1, 2.3 Hz, 1H), 6.17 (s, 1H), 2.53 (d, J=1.0 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[C:9]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC[C@@H](CO)O1
Solvent: O
Solvent: c1ccncc1
Product: O=C1CC[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
105.5 g of (5S)-5-(hydroxymethyl)tetrahydro-2-furanone was dissolved in 1.2 L pyridine, and 380 g of trityl chloride was added thereto at room temperature, and the mixture was stirred at 80° C. overnight. After the reaction was completed, the mixture was cooled, water was added thereto, extracted with ethyl acetate, and then washed with brine. The solvent was removed, and the resulting residue was dissolved in 300 ml chloroform, and after 600 ml silica gel was added thereto, the solvent was removed. The resulting residue was purified by silica gel column chromatography to give 149.3 g of (5S)-5-[(trityloxy)methyl]tetrahydro-2-furanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:33])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH:30]([CH3:32])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[C:34](Cl)([Cl:36])=[O:35]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:33])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:34]([Cl:36])=[O:35])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH:30]([CH3:31])[CH3:32])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2)c(OC(C)C)c1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:31]([F:34])([F:33])[F:32])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29]C)=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([C:31]([F:34])([F:32])[F:33])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CN(Cc2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CC(C(=O)O)C4)ccc3c2C(F)(F)F)CC1
Temperature: 0 °C

Procedure:
To a solution of methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate (100 mg, 0.25 mmol) in ethanol (10 mL) was added aqueous NaOH (3 mL, 20%) and refluxed for 1 h. Then the reaction was cooled to 0° C., the pH of the solution was adjusted to 6 with 1 M HCl, and concentrated. The residue was dissolved in dichloromethane, washed with water, dried and concentrated to give 1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid as a white solid (70 mg, yield: 70%). ESI-MS: 464.2. (M+H)+. HPLC: 98.64% 1H NMR (400 MHz, DMSO-d6) δ: 8.19 (d, 2H), 8.08 (d, 2H), 7.72 (d, 1H), 7.67 (d, 1H), 4.60-4.58 (m, 1H), 4.51 (s, 2H), 4.21 (d, 4H), 3.55-3.67 (m, 1H), 2.13 (d, 2H), 1.80 (d, 2H), 1.35-1.43 (q, 2H), 1.03-1.22 (m, 3H), 0.86 (s, 9H).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][C@H:18]([CH2:23][O:24][CH3:25])[C:19]([F:22])([F:21])[F:20])[C:14]([N+:26]([O-])=O)=[C:13]([F:29])[CH:12]=2)[CH2:6][S@@:5](=[O:30])[CH2:4]1.[CH3:31][C:32]([CH3:42])([CH3:41])[CH2:33][C:34]1[O:38][N:37]=[C:36]([CH:39]=O)[CH:35]=1.Cl>CCOCC>[ClH:1].[ClH:1].[NH2:26][C:14]1[C:15]([O:17][C@H:18]([CH2:23][O:24][CH3:25])[C:19]([F:22])([F:20])[F:21])=[CH:16][C:11]([CH2:10][C@H:7]2[C@H:8]([OH:9])[C@@H:3]([NH:2][CH2:39][C:36]3[CH:35]=[C:34]([CH2:33][C:32]([CH3:42])([CH3:41])[CH3:31])[O:38][N:37]=3)[CH2:4][S@:5](=[O:30])[CH2:6]2)=[CH:12][C:13]=1[F:29]
Reactant: CC(C)(C)Cc1cc(C=O)no1
Reactant: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](N)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Agent: Cl
Solvent: CCOCC
Product: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NCc3cc(CC(C)(C)C)on3)[C@H]2O)cc(F)c1N)C(F)(F)F

Procedure:
The title compound can be prepared in an analogous manner as described for example 41 steps c) and d) from (1R,3R,4S,5S)-3-amino-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol hydrochloride and 5-(2,2-dimethyl-propyl)-isoxazole-3-carbaldehyde and subsequent transformation into the hydrochloride salt with 5N HCl in Et2O to afford the title compound as a beige foam: TLC (CH2Cl2-MeOH 9:1) Rf=0.53; HPLC RtG3=1.77 min; ESIMS [M+H]+=566; 1H NMR (400 MHz, DMSO-d6): δ 6.73 (s, 1H), 6.64 (d, 1H), 6.25 (s, 1H), 5.12-5.06 (m, 1H), 4.99 (d, 1H), 4.59 (s, 2H), 3.83-3.68 (m, 4H), 3.33 (s, 3H), 3.17-3.06 (m, 3H), 3.00-2.97 (m, 1H), 2.72-2.68 (m, 1H), 2.63 (s, 2H), 2.45-2.27 (m, 4H), 0.93 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:43])[NH:41]O)=[CH:36][CH:35]=1>CC#N>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:43]=[C:13]([CH:12]([N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[CH3:16])[O:15][N:41]=2)=[CH:36][CH:35]=1
Reactant: N=C(NO)c1ccc(F)cc1
Reactant: CC(C(=O)O)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(c1nc(-c2ccc(F)cc2)no1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.7 %

Procedure:
To 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]propanoic acid (0.06 g, 0.212 mmol) in CH3CN (3 mL) was added CDI (0.034 g, 0.212 mmol). After 5 min, 4-fluoro-N-hydroxybenzenecarboximidamide (0.033 g, 0.212 mmol) was added. The resulting mixture was stirred at rt and then heated to 150° C. in a microwave for 20 min. Concentration was followed by column chromatography (EtOAc/hexanes) to obtain the desired product (0.0065 g, 8% yield): MS (APCl) m/z 401 (M+1).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[N:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[N-:63][CH3:64].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[N-:63][CH3:64]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[N-]c1ccccn1
Agent: On1nnc2ccccc21
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 130 mg of Z-Phe-His-OH, 100 mg of H-Leu-Val-Ile-2-pyridyl-methyl amide, 46 mg of HOBt and 62 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.32.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2C(=O)C3=CC=CC=C3C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH2:7][O:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1ccccc1

Procedure:
When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1 -dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].CCO>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(B(O)O)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 85 °C
Yield: 95 %

Procedure:
A stirred mixture of 3-chloro-5-(dihydroxyboryl)-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (200 mg, 0.50 mmol; see step (b) above), 2-bromo-5-(trifluoromethyl)pyridine (170 mg, 0.75 mmol), sodium carbonate (2M in water, 0.75 mL, 1.5 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), EtOH (0.4 mL) and toluene (1.6 mL) was heated at 85° C. for 3 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, concentrated and purified by chromatography to give the sub-title compound (239 mg, 95%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH2:28][C:29]([O:31]C)=[O:30])=[C:20]2[CH3:33])=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O1CCCC1>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH2:28][C:29]([OH:31])=[O:30])=[C:20]2[CH3:33])=[CH:34][CH:35]=1)=[O:12]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2ccccc2n1Cc1ccc(NC(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
Into a dry reaction vessel, methyl 2-[1-[4-(2-naphthamido)benzyl]-2-methyl-1H-indol-3-yl]acetate (150 mg, 0.324 mmol), lithium hydroxide monohydrate (55 mg, 1.31 mmol), 3 mL tetrahydrofuran, 3 mL water were weighed, and stirred at room temperature for 2 h. The reaction was monitored to be complete by TLC. The solvent was rotate evaporated. It was adjusted to pH=3-4 with 2 N HCl solution. It was extracted by ethyl ester, rotate evaporated to dryness to obtain the product as a white solid 80 mg. After recrystallization by ethyl acetate, a pure product 51 mg was obtained, at a yield of 35.2%.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: CCc1ccc(Cl)cc1
Reactant: O=S(=O)(O)Cl
Product: CCc1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22.9 %

Procedure:
Chlorosulfonic acid (4.0 mL, 59 mmol) was cooled to 0° C. and 1-chloro-4-ethylbenzene (1.0 mL, 7.5 mmol) was added dropwise over 30 min. The reaction mixture was stirred for 45 min at 0° C., poured with stirring onto 125 mL of crushed ice, and then extracted with ethyl acetate (2×100 mL). The ethyl acetate layers were combined, washed with water (100 mL), and dried over magnesium sulfate. The ethyl acetate was concentrated under reduced pressure to obtain an oil determined to be approximately a 1:1 mixture of isomers. This mixture was chromatographed on silica gel eluting with a hexane/ethyl acetate gradient to afford 0.41 g of the title compound. 1H NMR (CDCl3) δ 7.97 (s, 1H), 7.53 (d, 1H), 7.49 (d, 1H), 2.75 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:13]([O:15]C)=[O:14])[CH:12]=1)[N:9](C(OC(C)(C)C)=O)[CH:8]=[C:7]2[CH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1.BrC1C=C2C(=C(C(OCC)=O)C=1)N(C(OC(C)(C)C)=O)C=C2C1CCS(=O)(=O)CC1>CO.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:13]([OH:15])=[O:14])[CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:24]1[CH2:25][CH2:26][S:27](=[O:30])(=[O:31])[CH2:28][CH2:29]1
Reactant: COC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)cn(C(=O)OC(C)(C)C)c12
Agent: CCOC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)cn(C(=O)OC(C)(C)C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 85 °C

Procedure:
A solution of 6 M NaOH (12 mL, 72.0 mmol) was added to a suspension of 1-(1,1-dimethylethyl) 7-methyl 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-1,7-dicarboxylate (0.93 g, 1.912 mmol) and 1-(1,1-dimethylethyl) 7-ethyl 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-1,7-dicarboxylate (3.08 g, 6.16 mmol) in MeOH (50 mL) and water (25 mL) in a 250 mL round bottomed flask fitted with a reflux condenser. The reaction was heated at 85° C. (bath temp) for 1.5 h. The MeOH was removed by rotovap, and a solution of 6 M HCl was added until the mixture had attained a pH of ˜1 by pH paper. The yellow solid was filtered off, and the filtrate was extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure, and the residue was combined with the precipitate from the filtration and dried under house vacuum at 45° C. overnight. Recovered 2.98 g (86%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[CH:4][N:3]=1.[IH:10]>C(Cl)Cl>[I:10][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: CSc1cc(Cl)ncn1
Reactant: I
Solvent: ClCCl
Product: CSc1cc(I)ncn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-chloro-6-methylsulfanyl-pyrimidine (0.54 g, 3.4 mmol), 57% hydriodic acid solution (2.50 mL, 19.0 mmol) and DCM (3 mL) was stirred at room temperature. After 5 h, the resultant solid was collected by filtration and washed with DCM. The cake was dissolved in water (10 mL) and basified with saturated aqueous sodium bicarbonate solution to pH=8. The aqueous layer was extracted with DCM (2×50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated to afford the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].CCOCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:30][CH2:29][C:28]([O:27][CH3:26])=[O:31])=[O:24]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc2ccccc2n1C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
DMAP (1.222 g, 0.01 mol) and EDAC (2.680 g, 0.014 mol) were added as solids to a solution of 1-methylindole-2-carboxylic acid (1.752 g, 0.01 mol) and glycine methyl ester hydrochloride (1.256 g, 0.01 mol) in methylene chloride (30 mL) and DMF (5 mL) under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and then for 3 hours at room temperature. The reaction mixture was partitioned with ethyl acetate and 5% KHSO4 solution and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) solution and brine, dried over sodium sulfate, and concentrated to give a purple powder as crude product. Trituration of the powder with ether afforded the title product (1.734 mg, 70%). TLC(methanol/methylene chloride 1:9): Rf =0.61; 1H-NMR (CDCl3): δ 7.65 (dt, J=8.0, 1.1, 1H), 7.41-7.31 (m, 2H), 7.16 (dd, J=6.6, 1.4, 1H) 6.96 (d, J=0.5, 1H), 6.67 (bs, 1H), 4.25 (d, J=5.2, 2H), 4.05 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH3:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]([CH:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:10]=[CH:9][C:8]([OH:7])=[CH:13][CH:12]=3)[CH2:19][CH2:18]2)[CH3:21])=[CH:23][CH:24]=1
Reactant: CN(c1ccc(Cl)cc1)C1CCN(c2ccc(OC3CCCCO3)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CN(c1ccc(Cl)cc1)C1CCN(c2ccc(O)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
1-(4-(Tetrahydropyran-2-yloxy)phenyl)-4-(N-(4-chlorophenyl)-N-methylamino)piperidine (1.33 g, 3.32 mmol) was suspended in ethanol (80 ml). To this mixture, pyridinium p-toluenesulfonate (0.25 g, 1 mmol) was added and then stirred at 70° C. for 8 hours. Ethanol was removed under reduced pressure, then to this residue, methylene chloride and a saturated aqueous sodium hydrogencarbonate solution were added and stirred. This was extracted with methylene chloride, dried over magnesium sulfate and then filtered. After the resulting filtrate was concentrated under reduced pressure, methylene chloride and n-hexane were added to the residue and the resulting precipitate was filtered to afford 4-(4-(N-(4-chlorophenyl)-N-methylamino)piperidine-1-yl)phenol (922.5 mg, yield 88%) as a light pink powder.
Reaction SMILES: C([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.[C:31]1(N)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN1CCCC1=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:16]2[C:15]([NH:5][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:25][CH:26]=1
Reactant: Nc1ccccc1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2Nc2ccccc2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with phenylamine ([62-53-3]) in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as brown solid. MS: m/e=320.1 [M+H+].
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CN.[BH4-].[Na+]>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH:24]([OH:26])[CH3:25])=[CH:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Agent: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the suspension of 1-{4-[2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-pyridin-4-yl]-phenyl}-ethanone (Example 7, 0.19 g, 0.55 mmol) in 2 mL of MeOH was added a solution of methylamine in MeOH (Aldrich Chemical Company) (2N, 0.55 mL, 1.1 mmol). The reaction was stirred at room temperature under nitrogen overnight. NaBH4 (Aldrich Chemical Company) (25 mg, 0.66 mmol) was then added to the reaction and it was stirred for another 5 hrs. The solvent was evaporated the residue was purified on a Biotage 40M column (97:3 dichloromethane:2N NH3 in MeOH) to give the title compound as an off-white foam. MS (ESI, pos. ion) m/z: 349 (M+1). Mp: 55.9-61.5° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1F
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 84.4 %

Procedure:
To a solution of 4-fluoro-3-(methyloxy)benzaldehyde (1.07 g, 6.94 mmol) and 3-(trifluoromethyl)phenol (1.238 g, 7.64 mmol) in DMF (25 mL) was added K2CO3 (2.88 g, 20.83 mmol) under argon. The mixture was heated at 90° C. for 0.5 h. After removing the solvent, the residue was diluted with water, extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated to afford the title compound (1.735 g, 5.86 mmol, 84% yield). LCMS: rt=3.53 min, [M+H+]=297