Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:10])[CH:3]=1.[C:11]([N:14]1[CH2:18][CH2:17][NH:16][C:15]1=O)(=[O:13])[CH3:12]>>[C:11]([N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[NH:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:10])[CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(N)n(C(C)C)n1
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1C(C)C

Procedure:
5-amino-1-isopropyl-3-methylpyrazole (J. Gen. Chem. USSR 31 234, 1961) (19.3 g.) and 1-acetyl-2-imidazolidinone (20.1 g.) were reacted as described in Example I to give 12.73 g. of product, mp 145°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1)[CH2:27][NH:28][CH3:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:37]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([CH:26]([OH:25])[CH2:27][N:28]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:22])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[CH:17]=2)[CH3:29])=[CH:31][CH:32]=1)(=[O:39])[CH3:38]
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNCC(O)c1ccc(NC(C)=O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(C(O)CN(C)Cc2cc3c(s2)c(=O)c(C(=O)NCc2ccc(Cl)cc2)cn3C)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 58.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), N-{4-[1-hydroxy-2-(methylamino)ethyl]phenyl}acetamide (42 mg, 0.20 mmol) and diisopropylethylamine (40 μL, 0.23 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with 3 mL of warming acetonitrile, cooled to room temperature, diluted with 2 mL of water, and then cooled to 0° C. overnight) gave the title compound (42 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)[CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.[CH3:28][Mg+].[Br-]>C1COCC1>[OH:8][C:7]([C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:10]=1)([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[CH3:28]
Reactant: C[Mg+]
Reactant: Cn1cncc1C(=O)c1ccc(C#N)c(Oc2ccc3ccccc3c2)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1cncc1C(C)(O)c1ccc(C#N)c(Oc2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
4-(3-Methyl-3H-imidazole-4-carbonyl)-2-(naphthalen-2-yloxy)-benzonitrile (0.109 g, 0.308 mmol) was dissolved in anhydrous THF (5 mL) and a 3.0 M solution of MeMgBr (0.35 mL, 1.05 mmol) was added and stirred at RT. The reaction was quenched with NH4Cl after 1 h, concentrated, diluted with EtOAc, washed with satd. NaHCO3 solution, water, brine, dried (MgSO4) and concentrated to give the title compound. FT/ICR MS (M+1)=370.
Reaction SMILES: [C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[N:15]([CH2:28][OH:29])[C:14]2=[O:30])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[CH2:31]([O:38][P:39](N)(=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1C=NN=N1.ClC1C=CC=C(C(OO)=O)C=1>O1CCCC1.ClCCl>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[N:15]([CH2:28][O:29][P:39](=[O:48])([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:38][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:14]2=[O:30])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: NP(=O)(OCc1ccccc1)OCc1ccccc1
Reactant: O=C1[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C(=O)N1CO
Agent: O=C(OO)c1cccc(Cl)c1
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C(=O)N1COP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(±)-Trans-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-1-hydroxymethyl-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione (0.06 g) in anhydrous tetrahydrofuran (5 ml) was treated with dibenzylphosphoramidate (0.156 ml, 3.5 equivalents) followed by the addition of tetrazole (3% solution in acetonitrile, 2 ml). The reaction mixture was stirred at room temperature for 20 min and cooled to −78° C. A solution of m-chloroperbenzoic acid (70%, 0.162 g) in dichloromethane (2 ml) was added at −78° C. After 5 min at −78° C., the reaction was brought to room temperature and stirred for 5 min. Solvents were removed under reduced pressure and the residue was purified by flash chromatography on a silica column, eluted with ethyl acetate, hexane to give phosphoric acid dibenzyl ester trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-dioxo-pyrrolidin-1-ylmethyl ester as a solid (70 mg). 1H NMR (DMSO-d6) 400 MHz δ: 11.10 (s, 1H), 7.32-7.39 (m, 12H), 6.84-7.24 (m, 2H), 5.49 (brs, 2H), 5.03 (m, 4H), 4.61 (dd, 2H), 4.06 (brs, 2H), 2.87 (brs, 2H), 2.07 (brs, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])[NH:3]1.C1C=CC2N(O)N=[N:26][C:24]=2C=1.C(Cl)CCl.CN>CN(C=O)C>[CH3:24][NH:26][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH2:10][C:2](=[O:1])[NH:3]3)[CH:12]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(=O)O)c2)N1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A mixture of 3-(2-oxo-2,3-dihydro-1H-indol-4-yl)benzoic acid (1.27 g, 5.0 mmol), HOBt (0.68 g, 5.0 mmol) and EDC (1.44 g, 7.5 mmol) in DMF (10 mL) was stirred at room temperature for 30 minutes. To the mixture was added methylamine (2M in THF, 3.75 mL, 7.5 mmol), it was then stirred at room temperature for overnight. Most of the solvent was removed under reduced pressure and the residue was diluted with sat. NaHCO3 (20 mL). The precipitate was collected by filtration, washed with water and dried. The crude product was recrystallized from DCM-hexane to give 1.14 g (86%) of N-methyl-3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzamide as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11].C(N(CC)CC)C.C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:14][CH:13]([O:16][CH2:17][CH3:18])[O:12][CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)cc1Br
Reactant: CCOC(CBr)OCC
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(CNc1ccc(C)c(Br)c1)OCC
Temperature: 150 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Under a nitrogen stream, a mixture of 3-bromo-4-methyl-phenylamine (4.94 g, 26.55 mmol), bromoacetaldehyde diethyl acetal (6.80 g, 34.50 mmol), triethylamine (5.37 mL, 38.53 mmol) and ethanol (10.3 mL) was stirred for 2 hours at 150° C. using a microwave apparatus. The resultant solution was cooled to room temperature, and then water was added thereto. The resultant mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (1:10)), to thereby obtain the titled compound (6.43 g, 80%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@H:19]([CH3:22])CO)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:24].CC1C=CN=C(N)[C:36]=1[CH3:42].[C-]#N.[Na+]>ClCCl.O>[Si:1]([O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@H:19]([CH3:22])[CH2:42][CH:36]=[O:24])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: Cc1ccnc(N)c1C
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H](CC=O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The compound (S)-2-[(1R,3aR,4S,7aR)-4-(tert-Butyl-dimethylsilanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-ol (5.00 g; 15.31 mmol) is dissolved in dichloromethane (75 ml) at room temperature. Tosyl chloride (8.76 g; 45.93 mmol; 3 equivalents) and dimethyl-aminopyridine (5.61 g; 45.93 mmol; 3 equivalents) are added. The mixture is allowed to react over night. The reaction mixture is poured on brine and extracted with ethyl-acetate. The organic phase is dried over sodium sulfate and the solvents are removed. The crude tosylate is directly used in the next step. The intermediate tosylate is dissolved in DMSO (35 ml), NaCN (2.25 g; 45.93 mmol; 3 equivalents) is added and heated for 2 hours at 90° C. The reaction mixture is poured in water and extracted with hexane/ethyl-acetate 1:1. The organic phase is dried over sodium sulfate and the solvents are removed. The crude cyanide is directly used in the next step. The intermediate cyanide is dissolved in dichloromethane (50 ml), DIBAH is added slowly at -10° C. (38.3 ml of a 1.2 M solution; 45.93 mmol; 3 equivalents) and stirred for 2 hours at -10° C. The temperature is allowed to raise above the freezing point and a 1 M aqueous solution of ammonium chloride is added. After 10 minutes a 2:1 ether/1 N aqueous HCl (30 ml) is added and allowed to react for 15 minutes. The reaction mixture is extracted with ethyl-acetate. The organic phase is dried over sodium sulfate and the solvents are removed. After flash-chromatography (hexane/ethyl-acetate 95:5) (R)-3-[(1R,3aR,4S,7aR)-4(tert-Butyl-dimethylsilanyloxy)-7a-methyl-octahydro-inden-1-yl]-butan-1-al is obtained as a colorless waxy solid.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[CH2:7]=[C:8]1O[C:10](=[O:11])[CH2:9]1>>[C:4]([CH:3]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:7])[N:1]=[C:2]1[CH3:6])#[N:5]
Reactant: C/C(N)=C/C#N
Reactant: C=C1CC(=O)O1
Product: CC1=CC(=O)C(C#N)C(C)=N1

Procedure:
3-Cyano-2,6-dimethylpyrid-4-one was prepared from 3-aminocrotononitrile and diketene following the procedure of Kato et al (Yakugaku Zasshi 91, 740, 1971).
Reaction SMILES: [Si]([N:8]1[C@H:11](O[Si](C)(C)C)[C@@H:10]([C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])[C:9]1=[O:27])(C(C)(C)C)(C)C.C(Cl)Cl.CN(C1C=CC=CN=1)C.C(OC(=O)C)(=O)C>CCCCCC>[Si:20]([O:19][C@@H:17]([CH:10]1[CH2:11][NH:8][C:9]1=[O:27])[CH3:18])([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CN(C)c1ccccn1
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)C1CNC1=O

Procedure:
There was dissolved 1 g of (3R,4R)-1-tert-butyldimethylsilyl-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one into 10 ml of methylene chloride, thereto 0.85 g of dimethylaminopyridine and 0.71 g of acetic anhydride were added and the mixture was reacted for one day at 0° C. After the reaction mixture was diluted with hexane and washed successively with 5% aqueous solution of NaHCO3, an aqueous solution of hydrochloric acid of pH 4 and saturated solution of salt, the resultant was dried with magnesium sulfate and the solvent was distilled away to give 0.85 of a liquid crude product. The obtained liquid was purified by a silica-gel column chromatography (hexane:ether=30:1) to give 0.40 g of (3R,4R)-4-acetoxy-1-tert-butyldimethylsilyl)-3-[(R)-1-tert-butyldimethylsilyloxyethyl)azetidin-2-one as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[CH2:18][C:17](=[O:19])[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].[Cs+]>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[CH2:18][C:17]([OH:19])([C:23]([F:25])([F:24])[F:22])[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC(=O)C[C@@H]12
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC(O)(C(F)(F)F)C[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-4-((3S,3aS)-3-methoxy-5-oxo-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile prepared according to example 9 (10 mg, 0.033 mmole) in THF (3 mL) at 0° C. was added trifluoromethyl-trimethyl silane (0.02 mL, 0.0396 mmol) followed by the addition of CsF (0.5 mg, 0.0033 mmol) and the reaction mixture was stirred at room temperature for 3 h. Once the starting material had disappeared (monitored by TLC), the reaction mixture was quenched with 4N HCl and extracted with diethyl ether. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by preparative TLC method (2% MeOH in DCM) provided the title compound.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[NH2:31]>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Nc1cc(F)ccc1F
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2cc(F)ccc2F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,5-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.35 (s, 3H), 4.75 (d, J=4.8 Hz, 2H), 5.96 (bs, 1H), 6.656-6.62 (m, 1H), 6.67 (bs, 1H), 7.01 (m, 1H), 7.16 (t, J=5.4 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 8.29 (bs, 1H), 8.59 (d, J=3.4 Hz, 1H); MS (ESI) m/z 342.7 (M+1)+.
Reaction SMILES: N#N.[H-].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12](N(C)C)[C:13]#N)=[CH:8][CH:7]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23](CCl)=[CH:22][CH:21]=1.S(=O)(=O)(O)[OH:31]>O.CN(C)C=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:31])[CH2:13][C:23]2[CH:26]=[CH:27][C:20]([C:19]([F:29])([F:28])[F:18])=[CH:21][CH:22]=2)=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CN(C)C(C#N)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Yield: 96.7 %

Procedure:
Into a 2 l four-necked flask equipped with a thermometer, a stirrer, a dropping funnel and a N2 gas supply tube, a N2 gas was supplied so that the interior of the flask became a N2 atmosphere. 400 ml of dimethylformamide and 35.0 g (0.9 mol) of sodium hydride (62% oil suspension) were charged, and a mixed solution comprising 133.5 g (0.75 mol) of 2-(4-fluorophenyl)-2-(N,N-dimethylamino)acetonitrile, 145.9 g (0.75 mol) of 4-(trifluoromethyl)benzyl chloride and 280 ml of dimethylformamide, was dropwise added over a period of one hour at from 10 to 25° C. under cooling with water and then further reacted at from 20 to 30° C. for one hour. Then, 330 g of 40% sulfuric acid aqueous solution was added to this reaction mixture and reacted at from 80 to 90° C. for one hour. After completion of the reaction, the reaction product was added to 2 e of water, and precipitated crystals were collected by filtration under reduced pressure and washed with water. Then, the crystals were washed and purified at 20° C. by means of 500 ml of isopropyl alcohol and then dried with hot air to obtain 204.7 g (yield: 95.2%) of the desired compound having a purity of 98.4% (by HPLC analysis).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])(C)(C)C.[CH3:16][N:17]1[CH2:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[S:9]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:2]([C:25]3([OH:27])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][N:17]([CH3:16])[CH2:26]3)[CH:3]=[CH:4][C:5]1=2.[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:25]3([OH:27])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][N:17]([CH3:16])[CH2:26]3)=[CH:7][C:6]=2[CH:10]=1
Reactant: Brc1ccc2sccc2c1
Reactant: CN1CC(=O)c2ccccc2C1
Agent: [Li]C(C)(C)C
Product: CN1Cc2ccccc2C(O)(c2cc3cc(Br)ccc3s2)C1
Product: CN1Cc2ccccc2C(O)(c2ccc3sccc3c2)C1
Temperature: -75 °C
Reaction time: 1 h
Yield: 11 %
Yield: 8 %

Procedure:
To a solution of 5-bromobenzothiophene (511 mg, 2.4 mmol) at −75° C., was added t-butyllithium (1.7 M in pentane, 1.6 mL, 2.6 mmol) dropwise. The reaction mixture was stirred at −75° C. for 1 hour. To the resulting dark brown mixture was added 2-methyl-2,3-dihydro-1H-isoquinolin-4-one (323 mg, 2.0 mmol), which was prepared using the method described by Hanna et al., J. Med. Chem., 17(9):1020-1023 (1974), which is hereby incorporated by reference in its entirety. The reaction mixture was stirred for 15 hours with gradual warming up. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by medium pressure silica gel chromatography (10-40% ethyl acetate/hexanes) followed by preparative HPLC afforded 4-(benzo[b]thiophen-5-yl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-ol (65 mg, 11%) and 4-(5-bromobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol (58 mg, 8%). 4-(Benzothiophen-5-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol: 1H NMR (CDCl3, 500 MHz) δ 7.81 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.34-7.23 (m, 4H), 7.20 (s, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 3.91 (s, 1H), 3.84 (d, J=15.0 Hz, 1H), 3.53 (d, J=15.0 Hz, 1H), 3.11 (dd, J=11.6, 1.4 Hz, 1H), 2.87 (d, J=11.6 Hz, 1H), 2.50 (s, 3H); ESI MS m/z=296 [M+H]+. 4-(5-Bromobenzothiophen-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol: 1H NMR (CDCl3, 300 MHz) δ 7.81 (d, J=1.8 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.30-7.23 (m, 2H), 7.18 (d, J=7.3 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.69 (d, J=15.0 Hz, 1H), 3.48 (d, J=15.0 Hz, 1H), 3.10 (dd, J=11.6, 1.3 Hz, 1H), 2.83 (d, J=11.6 Hz, 1H), 2.47 (s, 3H); ESI MS m/z=374 [M+H]+.
Reaction SMILES: C[C@H](N)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:15]([C@H:17]1[CH2:25][CH:24]=[CH:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)=O.[ClH:31].Cl.[NH:33]1[CH2:38][CH2:37][CH:36]([NH:39][NH2:40])[CH2:35][CH2:34]1.C(N(CC)CC)C>C(O)CC>[ClH:31].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:15]2[C@@H:17]3[C@@H:18]([CH2:22][CH:23]=[CH:24][CH2:25]3)[C:19](=[O:21])[N:39]([CH:36]3[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]3)[N:40]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: NNC1CCNCC1
Reactant: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OC
Agent: C[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCCO
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Temperature: 25 °C

Procedure:
A solution of 50 mmol of the salt of (S)-(−)-α-methylbenzylamine and (cis)-2-(3,4-dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (starting compound A8), 55 mmol of piperidin-4-yl-hydrazine dihydrochloride and 100 mmol of triethylamine in 150 ml of 1-propanol is refluxed for 18 h. After cooling to RT, the precipitate is filtered off and dried. M. p. 285-288° C.
Reaction SMILES: F[C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@H:11]3[C@H:18]4[C@H:14]([O:15][C:16]([CH3:20])([CH3:19])[O:17]4)[C@@H:13]([CH3:21])[CH2:12]3)[C:6]=2[C:5]([F:22])=[CH:4][N:3]=1.F[C:24]1[C:29]2[N:30]([C@H:33]3[C@H:40]4[C@H:36]([O:37][C:38]([CH3:42])([CH3:41])[O:39]4)[C@@H:35]([CH3:43])[CH2:34]3)[CH:31]=[N:32][C:28]=2[C:27]([F:44])=[CH:26][N:25]=1>N>[F:22][C:5]1[C:6]2[N:10]([C@H:11]3[C@H:18]4[C@H:14]([O:15][C:16]([CH3:20])([CH3:19])[O:17]4)[C@@H:13]([CH3:21])[CH2:12]3)[CH:9]=[N:8][C:7]=2[C:2]([NH2:25])=[N:3][CH:4]=1.[F:44][C:27]1[C:28]2[N:32]=[CH:31][N:30]([C@H:33]3[C@H:40]4[C@H:36]([O:37][C:38]([CH3:42])([CH3:41])[O:39]4)[C@@H:35]([CH3:43])[CH2:34]3)[C:29]=2[C:24]([NH2:3])=[N:25][CH:26]=1
Reactant: C[C@H]1C[C@@H](n2cnc3c(F)cnc(F)c32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: C[C@H]1C[C@@H](n2cnc3c(F)ncc(F)c32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: N
Product: C[C@H]1C[C@@H](n2cnc3c(F)cnc(N)c32)[C@@H]2OC(C)(C)O[C@@H]21
Product: C[C@H]1C[C@@H](n2cnc3c(N)ncc(F)c32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 100 °C

Procedure:
Liquid ammonia (150 mL) was added to a mixture of 4,7-difluoro-1-((3aS,4R,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridine (6-3) (180 mg, 0.6 mmol, 1 equiv) and 4,7-difluoro-3-((3aS,4R,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-3H-imidazo[4,5-c]pyridine (6-4) (180 mg, 0.6 mmol, 1 equiv). The resulting solution was heated in a high pressure vessel to 100° C. for 2 days. The mixture was then concentrated and purified by flash chromatography (12 g SiO2; 20-100% EtOAc in hexanes and then 100% ethanol to elute 6-3) to yield 7-fluoro-1-((3aS,4R,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine (6-5) as a tan solid and 7-fluoro-3-((3aS,4R,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-3H-imidazo[4,5-c]pyridin-4-amine (6-6) as a tan solid. LRMS m/z (M+H) 306.9 found, 307.1 required.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C:23](=[O:47])[CH:24]2[CH2:29][CH2:30][O:31][C:32](=[O:46])[N:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:48][Mg]Br.C(OCC)(=O)C.O>O1CCCC1>[Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C:23]([OH:47])([CH3:48])[CH:24]2[CH2:29][CH2:30][O:31][C:32](=[O:46])[N:33]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(=O)C2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(O)CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1CCOC(=O)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-t-butyldiphenylsilyloxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-2-oxo-1,2,3,4-tetrahydronaphthalene (0.9 g) in THF (tetrahydrofuran) (20 ml) was added methylmagnesium bromide (2.0 ml, 1M solution in THF) at 0° C. under N2. After being stirred for 1 hour at the room temperature, the solution was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 5-t-butyl-diphenylsilyloxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-2-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalene (0.6 g).