Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH:12]([CH3:26])[C:13](=[O:25])[N:14]([CH2:16][CH2:17][O:18]C3CCCCO3)[CH2:15][C:9]=2[CH:8]=1>ClCCl>[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH:12]([CH3:26])[C:13](=[O:25])[N:14]([CH2:16][CH2:17][OH:18])[CH2:15][C:9]=2[CH:8]=1
Reactant: CC1Cc2ccc(Cl)cc2CN(CCOC2CCCCO2)C1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1Cc2ccc(Cl)cc2CN(CCO)C1=O
Yield: 10 %

Procedure:
150 ml. of 20% sulfuric acid are added, with vigorous stirring, to a solution of 2.9 g. (0.0086 moles) of 8-chloro-4-methyl-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one in 50 ml. of dichloromethane. When the addition is complete, stirring is continued for 2 at room temperature. After decantation, the organic phase is washed neutral with water, dried over anhydrous sodium sulfate and then evaporated to dryness in vacuo. The solid residue is purified by chromatography on a silica column and then by recrystallization from methanol. 8-Chloro-2-(2-hydroxyethyl)-4-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one is obtained in a yield of 10% of theory. M.P. 139°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15]([O:17]CC)[CH3:16].C(OC(=O)C)(=O)C>CCCCCC>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1ccc(NC(C)=O)cc1

Procedure:
A sample of 50 g. of ethyl p-aminocinnamate is dissolved in 500 ml. of ethyl ether and a solution of 28 g. of acetic anhydride in 30 ml. of ether is added dropwise. When the addition is complete, the reaction is allowed to stir for another hour. The mixture is then diluted with hexane and filtered, providing ethyl p-acetamidocinnamate.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4](=[O:19])[CH2:5][CH:6]1[NH:11][CH2:10][CH2:9][N:8]2[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=[C:7]12.[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31]([N:11]1[CH2:10][CH2:9][N:8]2[N:12]=[C:13]([C:15]([F:17])([F:16])[F:18])[N:14]=[C:7]2[CH:6]1[CH2:5][C:4]([N:3]([CH3:2])[CH3:20])=[O:19])=[O:32])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)CC1NCCn2nc(C(F)(F)F)nc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Product: CN(C)C(=O)CC1c2nc(C(F)(F)F)nn2CCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C

Procedure:
A 200 mg portion of 8-[2-(dimethylamino)-2-oxoethyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine, hydrochloride was coupled to (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid essentially following the procedure outlined in Example 2, Step D. Purification by preparative TLC (silica gel, 10% methanol/dichloromethane) followed by HPLC (AD chiral pak column, 15% isopropanol/heptane) separated the first and last eluting diastereomers. LC/MS 593 (M+1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (118 mg, 89%), MS (ISP) m/z=443.5 [(M+H)+], mp 236.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[CH3:27].CN([CH:31]=[O:32])C>C1COCC1>[Br:16][C:17]1[C:18]([CH3:27])=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][C:22]=1[CH:31]=[O:32]
Reactant: Cc1cc(C(F)(F)F)ccc1Br
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)cc(C=O)c1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
To a 100 mL round bottom flask were added 2,2,6,6-tetramethylpiperidine (2.8 mL, 16.6 mmol), and 50 mL THF. BuLi (9.5 mL, 15.2 mmol, 1.6 M hexane solution) was added via a syringe at 0° C. After stirring at 0° C. for 15 mins, ice bath was replaced with dry ice/ether bath. To another 25 mL round bottom flask was added 1-bromo-2-methyl-4-(trifluoromethyl)benzene (3.3 g, 13.8 mmol) and THF. After cooling with dry ice/acetone bath, this solution was cannular transferred to the first flask rapidly. Upon completion of transferring, DMF (2.1 mL, 27.6 mmol) was added immediately and the resulting reaction mixture was stirred at that temperature for 10 more minutes before it was allowed to warm to −20° C. slowly. The reaction was quenched at −20° C. with addition of 50 mL 1N HCl. This mixture was diluted with 100 mL water and extracted with 100 mL EtOAc/hexane 1:9. The organics were washed with 30 mL NaHCO3 aqueous solution, dried over sodium sulfate, filtered and concentrated. Crude product was purified by chromatography to give 1.8 g 2-bromo-3-methyl-5-(trifluoromethyl)benzaldehyde. 1H NMR (500 MHz, CDCl3) δ10.50 (s, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 2.60 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16](=O)[C:15]2[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][CH:8]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16]2=[N:30][NH:31][C:18](=[O:20])[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=32)[NH:9][CH:8]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
A mixture of ethyl 3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (140 mg) in 85% hydrazine monohydrate (3 mL) and methanol (5 mL) was stirred at room temperature for 2 days. The resulting mixture was filtered and the residue was washed with water (20 mL) and methanol (5 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (95 mg, yield 74%). 1H-NMR (400 MHz, DMSO-d) δ (ppm): 3.40 (s, 3H), 4.64-4.67 (d, J=10.8 Hz, 1H), 4.92-4.94 (d, J=10.4 Hz, 1H), 6.72 (s, 1H), 6.87 (s, 1H), 7.15-7.17 (d, J=8.4 Hz, 2H), 7.26-7.30 (m, 3H), 7.38 (s, 3H), 7.55-7.59 (t, J=7.6 Hz, 1H), 12.15 (s, 1H); LC-MS (ESI) m/z: 344 (M+1)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[CH3:22][C:23]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([CH3:31])=[C:25]([CH3:32])[C:24]=1[S:33](Cl)(=[O:35])=[O:34].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][S:33]([C:24]1[C:23]([CH3:22])=[C:28]([CH3:29])[C:27]([CH3:30])=[C:26]([CH3:31])[C:25]=1[CH3:32])(=[O:35])=[O:34])=[N+:2]=[N-:3]
Reactant: Cc1c(C)c(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C)c(C)c(S(=O)(=O)NCCN=[N+]=[N-])c(C)c1C
Yield: 81 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2,3,4,5,6-pentamethylbenzene-1-sulfonyl chloride (0.304 g, 1.23 mmol) was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and triethylamine (0.249 g, 2.46 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide (0.296 g, 81% yield). 1H NMR (300 MHz, CDCl3) δ 5.12 (t, J=3.9 Hz, 1H) δ 3.35 (t, J=5.4 Hz, 2H), δ 3.05 (q, J=6.0, 5.1 Hz, 2H), 2.59 (s, 6H), δ 2.28 (s, 3H), 2.24 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 139.9, 136.1, 135.2, 134.2, 51.1, 42.3, 19.2, 17.9, 17.3 ppm; HRMS (ESI) calcd for C13H20N4O2S (M+) 296.1307. found 296.1304.
Reaction SMILES: C(C1[CH:36]=[C:35]([CH3:37])[C:6]([C:7]([NH:9][CH2:10][CH2:11][C@H:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:33]=3[CH3:34])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH3:13])=[O:8])=[C:5]([CH3:38])[CH:4]=1)#N.[OH-:39].[Na+].[CH3:41][CH2:42][OH:43]>>[CH3:37][C:35]1[CH:36]=[C:41]([CH:4]=[C:5]([CH3:38])[C:6]=1[C:7]([NH:9][CH2:10][CH2:11][C@H:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[CH3:34])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)[CH3:13])=[O:8])[C:42]([OH:39])=[O:43]
Reactant: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(C#N)cc2C)CC1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(C(=O)O)cc2C)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 4-cyano-2,6-dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidin-1-yl}-butyl)-benzamide (0.21 g, 0.41 mmol) in EtOH (10 mL) was added 3N NaOH (5 mL) and the resulting colourless solution was stirred at 100° C. for 18 h. The EtOH was removed in vacuo and the pH adjusted to ˜5 before dry loading onto silica gel. Purification by column chromatography on silica gel (8:1:1, CH3CN/MeOH/NH4OH) afforded 3,5-dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidin-1-yl}-butyl)-terephthalamic acid (0.23 g, 100%) as a white solid. 1H NMR (CD3OD) δ 1.43 (d, 3H, J=8 Hz), 1.91 (m, 1H), 2.14 (m, 3H), 2.22 (m, 1H), 2.32 (s, 6H), 2.41 (s, 2H), 3.34 (s, 5H), 3.45 (m, 4H), 3.53 (m, 1H), 4.20 (m, 1H), 4.48 (s, 2H), 6.79 (m, 3H), 7.19 (m, 3H), 7.66 (m, 2H), 8.23 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].Cl.[NH2:29][CH:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2>>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:29][CH:30]2[C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: NC1c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNC2c3ccccc3-c3ccccc32)cc1-c1ccccc1C

Procedure:
The desired compound was prepared using the method described in Example 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G, and 9-aminofluorene hydrochloride salt m/e (ESI) 551 (MH+)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C(F)(F)F)[C:11](C)=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.[C:38](O)([C:40]([F:43])([F:42])[F:41])=O>C(Cl)Cl>[CH3:12][C:11]1[C:38]([C:40]([F:43])([F:42])[F:41])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)N=C(c1cccc(-c3cnccn3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {4-methyl-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M85) (0.28 g, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (146 mg, 68%).
Reaction SMILES: [N:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:16])[C:6]([CH3:18])([CH3:17])[CH2:5]1)=[N+]=[N-].[H][H]>CCO.[Pd]>[NH2:1][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:16])[C:6]([CH3:18])([CH3:17])[CH2:5]1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C(N=[N+]=[N-])CC(C)(C)C2=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)C(N)CC(C)(C)C2=O
Reaction time: 5 h
Yield: 91.2 %

Procedure:
To a solution of 4-azido-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (2.50 g, 10.2 mmol) in EtOH (100 mL) at RT was added palladium on carbon (1.08 g, 10.2 mmol) in two portions. A hydrogen balloon was affixed to the reaction flask and the head space above the solvent was purged with H2. After 5 hours, the solution was filtered through a plug of celite and concentrated to provide the crude product as an oil. The residue was purified by column chromatography 100% DCM to 50% (10% MeOH/DCM/1% NH4OH) to provide the title compound as a yellow oil (2.04 g, 91% yield). MS m/z: 220.2 (M+1).
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]([C:16]#[N:17])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:18]([CH:6]1[CH2:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:16]#[N:17])[CH2:7]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CC(C#N)(c2ccccn2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC1(c2ccccn2)CC(N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
To a solution of 3-cyano-3-(pyridin-2-yl)cyclobutyl methanesulfonate (4.008 g, 15.89 mmol) in dry DMF (20 mL) was added sodium azide (2.066 g, 31.8 mmol), and the mixture was stirred in an oil bath at 90° C. for 48 hours under a N2 atmosphere. The reaction was diluted with EtOAc and water, and the layers were separated. The organic layer was washed with water and concentrated under vacuum. The residue was chromatographed on silica gel, eluting with 40% EtOAc/hexane to afford the title compound, a 3:1 mixture of geometrical isomers, as a colourless oil m/z 200 MH+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[NH2:19]>>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([NH:19][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([N:2]([CH3:1])[CH3:13])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:22]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C)c1ccc(O)c(C(=O)O)c1
Product: CN(C)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 28.8 %

Procedure:
Using 5-dimethylaminosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][CH2:34][NH2:35])[CH3:27]>>[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][CH2:34][NH:35][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CCC[C@@H]1CCN
Product: CCN1CCC[C@@H]1CCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 58, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67) and 2-((R)-1-ethylpyrrolidin-2-yl)ethylamine (Intermediate 141).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.Cl.[O:25]1CCOCC1>>[OH:20][C:16]1[CH:15]=[C:14]([C:12]2[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:25])[CH:7]=3)[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: C1COCCO1
Reactant: Oc1cccc(-c2nc(-c3ccnc(F)c3)c3sccc3n2)c1
Agent: Cl
Product: O=c1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)cc[nH]1

Procedure:
A mixture of 3-[4-(2-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-2-yl]-phenol, (60 mg), aqueous HCl (2M, 2 mL) and 1,4-dioxane (2 mL) was heated to reflux for 24 hours. Upon cooling, a precipitate formed; this was collected by filtration and washed with water and ether to yield the furnish the title compound (50 mg).
Reaction SMILES: [CH3:1][CH:2]([N:4]=[C:5]=[O:6])[CH3:3].[NH2:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][N:9]=1>O1CCCC1>[CH3:1][CH:2]([NH:4][C:5]([NH:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][N:9]=1)=[O:6])[CH3:3]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)c1cc(N)no1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 8 h

Procedure:
7.5 g of 1-methylethyl isocyanate was added to a stirred mixture of 6.2 g of 1A and 75 ml of tetrahydrofuran at room temperature, then the mixture was stirred at reflux temperature for 24 hours, when an additional 7.5 g of 1-methylethyl isocyanate was added and the mixture was stirred at reflux temperature for 24 hours. The mixture was concentrated to dryness to give a syrup. On standing overnight at room temperature, a solid formed. The solid was recrystallized from ether/hexane to give 1-(1-methylethyl)-3-(5-(1,1-dimethylethyl)-isoxazol-3-yl)urea (4A), as an off-white solid, m.p.: 135°-138° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9](=[O:12])[CH:10]=[CH:11][C:5]2=[CH:4][CH:3]=1.[O:13]1CCOCC1>C(Cl)Cl>[O:12]=[C:9]1[O:8][C:6]2=[N:7][C:2]([CH:1]=[O:13])=[CH:3][CH:4]=[C:5]2[CH:11]=[CH:10]1
Reactant: C1COCCO1
Reactant: Cc1ccc2ccc(=O)oc2n1
Solvent: ClCCl
Product: O=Cc1ccc2ccc(=O)oc2n1
Temperature: 160 °C
Yield: 40 %

Procedure:
To a solution of 7-methyl-2H-pyrano[2,3-b]pyridin-2-one (160 mg, 0.98 mmol) in 1,4-dioxane (12 mL) in a microwave reaction vial was added SeO2 (328 mg, 3.0 mmol). The reaction vial was capped and the mixture was heated in a microwave at 160° C. for 90 minutes. The reaction was diluted with DCM, filtered through a pad of Celite® and concentrated. The resulting material was dissolved in DCM and loaded onto a plug of silica gel and evaporated. Purification by column chromatography (silica gel) using a DCM/MeOH gradient (0-10% MeOH) provided the desired product as a pale yellow solid (120 mg, 40%). LCMS (ES+) m/z 176 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([C:15]([NH:17][CH3:18])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.CCCCO.Cl>CCOC(C)=O>[CH3:18][NH:17][C:15](=[O:16])[C:10]1[C:9]([NH:8][C:6]2[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[CH2:27]4)[CH:7]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNC(=O)c1ncccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1ncccc1Nc1cc(Nc2ccc3c(c2)CC(=O)N3)ncc1C(F)(F)F
Temperature: 160 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a high pressure vial was added 3-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylpicolinamide (0.205 g, 0.62 mmol) and 5-aminoindolin-2-one (0.138 g, 1.2 eq) and n-BuOH (5 mL). HCl (˜1.25M HCl in ethanol, 0.5 mL, 1.0 eq) was added to the above mixture. The vial was sealed and heated at 160° C. with stirring overnight in an oil bath. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude. The crude was dissolved in EtOAc and washed with saturated NaHCO3 solution. The organic layers were concentrated and the crude was purified by silica gel chromatography (20%˜100% EtOAc/Hex). The product was precipitated from EtOAc and filtered to obtain the desired product as the free base (isolated yield 56%). The product was converted to the HCl salt.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.[H][H]>C1COCC1.[Pd]>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[NH2:10]
Reactant: [H][H]
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(C)ccc1N
Yield: 99.7 %

Procedure:
A mixture of 5-methyl-2-nitroanisol (265 g, 1.58 mol) and 10% Pd/C (39.75 g) in THF (1.32 L) was stirred overnight at rt under 1 atm of hydrogen. Filtration over kieselguhr and evaporation afforded 216.1 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([S:29][CH3:30])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].N[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([S:29][CH3:30])=[N:23][C:24]=2[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)(=[O:3])[CH3:2]
Reactant: CSc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Reactant: NN1CCCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1nc(N2CCCCC2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
The above 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methylthio-9H-purine (1.83 g, 3.9 mmol) was dissolved in dioxan (40 ml) followed by 1-aminopiperidine (0.59 g, 5.85 mmol) and triethyl-amine (1.63 ml, 11.7 mmol). The reaction mixture was stirred at ambient temperature for 18 h, evaporated and purified by flash chromatography on silica gel. Elution initially with dichloromethane, followed by dichloromethane/methanol (100/1) provided 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2-methylthio-6-(1-piperidinyl)-9H-purine (1.24 g, 59%) as a foam. This compound was dissolved in methanolic ammonia (10 ml) and the solution was stirred at room temperature for 18 h, evaporated and purified by flash chromatography on silica gel. Elution initially with dichloromethane, followed by dichloromethane/methanol (19/1) gave 2-methylthio-N-(1-piperidinyl) adenosine (0.67 g, 55%) as a foam, 1H NMR (DMSO-d6) δ 2.51 (3H, s, --SCH3), 3.50-3.56 (1H, m, H-5'a), 3.62-3.68 (1H, m, H-5'b) 3.92 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.50 (1H, q, H-2'), 5.03 (1H, t, 5'-0H), 5.18, 5.44 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 8.24 (1H, s, H-8), 8.84 (1H, s, N--H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[OH:22][C:23]1[CH:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][N:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:29][C:27]5[CH:26]=[CH:25][NH:24][C:23](=[O:22])[CH:28]=5)[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=Cc1ccnc(O)c1
Product: O=c1cc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cc[nH]1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-hydroxypyridine-4-carbaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 4-[[5-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]methyl]-1H-pyridin-2-one.