Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:23]#N)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([O:19][CH:20]([F:22])[F:21])[CH:10]=2)[CH2:5][CH2:4]1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(O)[O-:38].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([O:19][CH:20]([F:22])[F:21])[CH:10]=2)([CH:23]=[O:38])[CH2:5][CH2:4]1
Reactant: O=S([O-])O
Reactant: COC1(OC)CCC(C#N)(c2ccc(OC(F)F)c(OC(F)F)c2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC1(OC)CCC(C=O)(c2ccc(OC(F)F)c(OC(F)F)c2)CC1
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one dimethyl ketal (1.5 g, 3.98 mmol) in toluene (50 mL) at room temperature under an argon atmosphere was treated with a solution of diisobutylaluminum hydride (1M in toluene, 10 mL, 10 mmol). After 4 h, a solution of saturated aqueous sodium bisulfite was added and the mixture was extracted twice with ethyl acetate. The combined organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (1.5 g, 99%).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([Cl:13])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:14]([Cu])#[N:15].CN(C=O)C>C(Cl)Cl>[Cl:13][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[C:11]=2[CH3:12]
Reactant: N#C[Cu]
Reactant: Cc1c(Br)ccc2cc(Cl)ncc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C#N)ccc2cc(Cl)ncc12
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 7-Bromo-3-chloro-8-methylisoquinoline (0.63 g, 2.4 mmol), CuCN (0.33 g, 3.7 mmol), and DMF (10 mL). The mixture was then refluxed at 150° C. overnight. When the reaction was complete, as evidenced by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered, re-dissolved in DCM, adsorbed into silica gel and purified by silica gel column chromatography (Hexanes:DCM→1:1) to provide the title product. LC/MS (IE, m/z): [M+1]+=203.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[C:27]1([CH:33]([CH3:37])[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([CH3:37])[C:34]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CC(C(=O)Cl)c1ccccc1
Solvent: CC(=O)O
Product: CC(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-phenyl-propionyl chloride. Off-white solid. MS (ESI): 447.3 (MH+).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[CH:31](O)(C)C>[Ni]>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:11]3[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=3[N:19]=[CH:31]2)[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(C)O
Reactant: CC(=O)OCC1CC(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])C(OC(C)=O)C1OC(C)=O
Agent: [Ni]
Product: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (2.75 g, 5.93 mmol) and Raney nickel (aqueous slurry, Aldrich, 300 mg wet) in isopropanol (250 mL) was shaken under hydrogen (40 psi) in a Parr shaker for 2.25 hours. Catalyst was filtered off with Celite and the filtrate acidified with 98% formic acid (5 mL) and concentrated to an orange oil. The oil was diluted with additional 98% formic acid (45 mL) and the resulting orange solution refluxed for 40 minutes. Volatiles were removed and the remaining dark oil dissolved in chloroform (100 mL). The chloroform solution was washed with saturated aqueous sodium bicarbonate (3×10 mL), dried (sodium sulfate), and evaporated to a foam which was chromatographed on silica gel. Title compound eluted with methanol:chloroform/3:97 as a white foam from ethyl acetate (2.26 g, 86%); 1H-NMR (DMSO-d6)δ: 8.57, 8.17, 7.97 (all s, 1 each, 3 benzimidazole CH), 5.6 (m, 1, CHO), 5.3-5.1 (m, 2, CHO and CHN), 4.35-4.15 (m, 2, CH2O), 2.6-2.4 (m overlapping solvent, 2 CH), 2.10, 2.06, 1.92 (all s) overlapped by 2.0 (m, total 10, 3CH3CO and CH).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)[NH:4][CH:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH3:1][C:2]1([CH3:26])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:15])([F:14])[F:16])[CH:9]=2)[NH:4][CH:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: CC1(C)C(O)c2cc(C(F)(F)F)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(C(F)(F)F)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a mixture of 3,3-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-ol (7.1 g, 19 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 3,3-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.4 g, 36%) as a white solid: LC/MS m/e calcd for C18H17F3N2O2 (M+H)+: 351.34, observed: 351.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=3)=[CH:29][C:28]=2[N:43]2[CH2:48][CH2:47]N[CH2:45][CH2:44]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.N1(C(OCC2C=CC=CC=2)=[O:56])CCNCC1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:37][CH:38]=3)=[CH:29][C:28]=2[N:43]2[CH2:44][CH2:45][O:56][CH2:47][CH2:48]2)[C:23]([F:25])([F:26])[F:24])[N:3]=1
Reactant: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(N3CCNCC3)c2)cc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(N3CCOCC3)c2)cc1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 36e) substituting morpholine for benzyl piperazine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]([OH:21])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)(Cl)=O.[NH:44]([CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH2:45][C:46]([O:48][CH3:49])=[O:47].C(N(CC)CC)C>C(Cl)Cl>[CH3:54][O:53][C:51](=[O:52])[CH2:50][N:44]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCCCCCCCCC
Reactant: COC(=O)CNCC(=O)OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(CC(=O)OC)CC(=O)OC)cc1OCCCCCCCCCCCCCC
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A solution of 0.8 g (1.46 mmol) of 3,4-bis(tetradecyloxy)benzoic acid and 20 ml of thionyl chloride was stirred at reflux for 3 hours. The excess thionyl chloride was removed at reduced pressure and the resultant acid chloride was dissolved in 10 ml of methylene chloride and 10 ml of anhydrous THF. This solution was added dropwise to a stirred, ice cooled mixture of 0.3 ml (1.86 mmol) of dimethyl iminodiacetate and 0.41 ml (2.9 mmol) of triethylamine in 10 ml of anhydrous methylene chloride. The cooling bath was removed after 30 minutes and the mixture was left at room temperature for 18 hours. The solvents were removed at reduced pressure and the residue was extracted with ethyl acetate. The extract was washed successively with 1N HCl, with NaHCO3 solution, dried and concentrated. Crystallization from ethyl acetate-hexane gave 0.905 g (90% yield, mp 70°-71°) of N-(2-methoxy-2-oxoethyl)-N-[3,4-bis(tetradecyloxy)benzoyl]glycine methyl ester.
Reaction SMILES: [P:1]([O-:44])([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)([O:3][CH2:4][CH:5]([O:26][C:27](=[O:32])[CH2:28][C:29]([CH3:31])=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[C:45](=O)([O-])O.[Na+]>CC(C)=O>[P:1]([O-:44])([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N+:39]1([CH3:45])[CH2:43][CH2:42][CH2:41][CH2:40]1)([O:3][CH2:4][CH:5]([O:26][C:27](=[O:32])[CH2:28][C:29]([CH3:31])=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCN1CCCC1)OC(=O)CC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCC[N+]1(C)CCCC1)OC(=O)CC(C)=O
Temperature: 50 °C
Reaction time: 13 h
Yield: 46 %

Procedure:
To 30 ml of acetone was dissolved 1.17 g (1.8 mmole) of 2-(acetoacetyloxy)-3-(octadecyloxy)propyl 5-(pyrrolidino)pentyl phosphate, and 820 mg (10 mmole) of sodium hydrogen-carbonate previously crushed in a mortar and 410 mg (2.2 mmole) of methyl para-tolanesulrte were added to the solution. The mixture was stirred at 50° C. for 13 hours and acetone was distilled off under reduced pressure. In 30 ml of water was dissolved the residue and the solution was adjusted to pH 4 with 2N HCl, followed by extraction with a mixture of dichloromethane and ethanol (10:1). The solvent was distilled off and the residue was purified by silica gel column chromatography [chloroform-methanol-water (65:25:4)] to give 550 mg yield: 46%) of the desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH:32]([CH3:34])[CH3:33])[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].ClC1[N:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][N:56]=1>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:39])[CH3:40])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH:32]([CH3:33])[CH3:34])[CH2:24][CH2:23][N:22]([C:25]5[N:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][N:56]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C(C)C)CCN(C(=O)OC(C)(C)C)CC4)cc3)oc12
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C(C)C)CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of tert-butyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)-4-isopropylpiperidine-1-carboxylate (35 mg, 0.064 mmol) in dichloromethane was added trifluoroacetic acid. The mixture was stirred overnight at room temperature and then concentrated in vacuo. To the residue were added of methanol (2 ml), potassium carbonate (45 mg, 0.326 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (16 μl, 0.133 mmol). The mixture was heated to 50° C. and stirred at this temperature for 4 h, at which point LC/MS analysis showed a peak at the desired molecular weight. The reaction mixture was concentrated and then purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (33 mg, 0.056 mmol, 87% yield). Mass spectrum (ESI) 591.1 (M+1). 1H NMR (500 MHz, CDCl3): 8.47 (d, J=4.5 Hz, 1H), 8.33 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 6.71 (d, J=5.0 Hz, 1H), 6.18 (br t, J=6.0 Hz, 1H), 4.18 (m, 2H), 3.65-3.75 (m, 4H), 3.47 (septet, J=7.0 Hz, 1H), 1.89 (septet, J=6.5 Hz, 1H), 1.70 (m, 2H), 1.50-1.60 (m, 2H), 1.46 (d, J=6.5 Hz, 6H), 1.02 (d, J=7.0 Hz, 6H).
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:15]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[C:9]1([S:8][C:4]2[N:3]([O:2][C:21]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:22])[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: On1ccnc1Sc1ccccc1
Agent: Cl
Product: O=C(On1ccnc1Sc1ccccc1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-2-phenylsulfanylimidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (98%, oil).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[CH3:13][C:14]1([CH3:23])[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=O)[CH2:15]1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:13][C:14]1([CH3:23])[C:15]2[C:4](=[O:6])[C:3]3[C:2](=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:1][C:16]=2[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19]1
Reactant: CCOC(=O)c1ccccc1N
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)Cc2[nH]c3ccccc3c(=O)c2C(C)(C)C1
Reaction time: 9 h
Yield: 18 %

Procedure:
1.49 ml (10 mmol) of ethyl 2-aminobenzoate and 1.73 ml (10 mmol) of 3,3,5,5-tetramethyl-cyclohexanone were mixed with 20 ml of toluene. 20 mg (0.1 mmol) of para-toluenesulfonic acid was added, and the reaction mixture was refluxed with continuous removal of the water produced in the reaction. After 9 h, toluene was removed under vacuum, and the residue was refluxed in 10 ml of phenyl ether. After cooling, the precipitate was filtered and washed with diethyl ether to obtain 1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9(10H)-acridone (18%). Following the procedure of Step 3 in Example 1, but substituting 1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9(10H)acridone for 9-(10H)acridone, gave 9-chloro-1,1,3,3-tetramethyl-1,2,3,4-tetrahydroacridine (21%), which was reacted with 4-(4-methylpiperazin-1-yl)aniline (according to the procedure of Step 4 in Example 1), to afford the title compound (3%, overall yield 0,1%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20]C(=O)OC(C)(C)C)[CH:12]=[N:13][C:14]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1>>[F:8][C:9]1[CH:10]=[C:11]([NH2:20])[CH:12]=[N:13][C:14]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1
Reactant: CC(C)(C)OC(=O)Nc1cnc(-n2nccn2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(-n2nccn2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
TFA (1 ml) was added to tert-butyl (5-fluoro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamate (30 mg) obtained in the 2nd step, followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure, a 5M sodium hydroxide aqueous solution was added to the obtained residue at 0° C. so as to alkalify the mixture, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and a light brown solid of 5-fluoro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (19 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Br-:9].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[CH:4][N:3]=1
Reactant: [Br-]
Reactant: Nc1ccnc(N)n1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: Nc1ncc(Br)c(N)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a mixture of 2,4-diaminopyrimidine (5.5 g, 0.05 mol, 1.0 eq.) and THF (200 ml) was added pyridinium tribromide (17.5 g, 0.055 mol, 1.1 eq) at 0° C. in three portions. The resulting mixture was stirred at about 0° C. for two hours, filtered and washed with THF (20 ml). The yellow solid was mixed with water (100 ml) and the resulting mixture was neutralized with 10% NaOH solution to a pH of about 7. Stirring was continued at room temperature for 30 minutes, after which the mixture was filtered, washed with water (2×20 ml) and dried under vacuum at 50° C. to give 8.2 g (87%) of 2,4-diamino-5-bromo-pyrimidine as a white solid. 1H NMR, HPLC and LCMS analyses of this product are identical to the product described in Step 1 of Example 1.
Reaction SMILES: Cl[C:2]1[C:3]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[N:7]=1.Cl.[CH3:24][O:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C(O)C>[CH3:24][O:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:3]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][S:14][C:4]=3[N:5]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[N:7]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)Cc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: COCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC1CCN(c2nc(CC(=O)O)nc3scc(-c4ccccc4)c23)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Ethyl 2-(4-chloro-5-phenyl-thieno[2,3-d]pyrimidin-2-yl)acetate (100 mg, 0.285 mmol), 4-(methoxymethyl)piperidine hydrochloride (52 mg, 0.314 mmol) and triethylamine (0.12 mL, 0.85 mmol) were dissolved in ethanol (4 mL) and heated to 65° C. for 6 hrs. The reaction was then heated to 150° C. in a microwave for 10 min. The reaction was poured over ice and extracted with DCM. The extracts were combined and concentrated in vacuo. The residue was dissolved in non-dry THF (2 mL) and lithium hydroxide monohydrate (48 mg) was added. The reaction was stirred at room temperature overnight then another portion of lithium hydroxide monohydrate was added (10 mg) and the reaction stirred for a further 2 hrs. The reaction mixture was purified on an Isolute NH2 SPE column (eluting ammonia in methanol) to give 2-[4-[4-(methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]acetic acid (107 mg).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([NH:13]C(=O)C)[CH:10]=[CH:9][C:8]=1[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:5].[Li+].[OH-].Cl>O1CCOCC1>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:7]([NH:6][C:4](=[O:5])[C:3]([OH:21])=[O:2])[CH:12]=1
Reactant: COC(=O)C(=O)Nc1cc(NC(C)=O)ccc1C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N)cc1NC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-(5-Acetylamino-2-tert-butyl-phenyl)-oxalamic acid methyl ester (1.28 g, 4.38 mmol) in 1,4-Dioxane (5 mL) at room temperature was added 1.05 equiv of 1.0N LiOH (4.60 mL, 4.60 mmol). After stirring at room temperature for 30 min, the reaction mixture was treated with 0.5N HCl (20 mL), stirred for 5 min and then partitioned between EtOAc/water. The organic phase was washed with saturated NaCl solution (50 mL), dried over Na2SO4 and evaporated to dryness. The oily residue was recrystallized from CH2Cl2/Hexane to give the title compound as a white fine crystal (1.74 g, 96%). 1HNMR (DMSO-d6) δ 10.05 (s, 1H), 9.96 (s, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.42 (dd, J=9.0, 2.1 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 2.02 (s, 3H), 1.30 (s, 9H); MS(ES) for C14H18N2O4 (MW=278.30): negative 277 ([M−H]−).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:22](/[CH3:30])=[C:23](/[F:29])\[C:24](OCC)=[O:25])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:22](/[CH3:30])=[C:23](/[F:29])\[CH2:24][OH:25])[CH3:2]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure L, ethyl (2E)-3-(7-ethoxy-2,2-dimethyl-4-phenyl-2H-chromen-6-yl)-2-fluoro-but-2-enoate (Compound 75, 160 mg, 0.38 mmol) and diisobutylaluminum hydride (1 M in hexanes, 1.51 mL, 1.51 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:4 ethyl acetate/hexane).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:12])[C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1.[Si:13]([O:20][CH2:21][CH2:22][C@@H:23]1[CH2:35][C:34]2[C:33]3[C:32](Cl)=[N:31][CH:30]=[N:29][C:28]=3[S:27][C:26]=2[CH2:25][CH2:24]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>O1CCCC1>[Si:13]([O:20][CH2:21][CH2:22][C@@H:23]1[CH2:35][C:34]2[C:33]3[C:32]([O:11][CH:8]4[CH2:9][CH2:10][CH:5]([N:4]([CH3:12])[CH3:3])[CH2:6][CH2:7]4)=[N:31][CH:30]=[N:29][C:28]=3[S:27][C:26]=2[CH2:25][CH2:24]1)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c2C1
Reactant: CN(C)[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
NaH (60% dispersion in mineral oil, 63 mg, 3.00 equiv) was treated with trans-4-(dimethylamino)cyclohexan-1-ol (104 mg, 0.73 mmol, 1.40 equiv) in distilled tetrahydrofuran (8 mL) at room temperature under nitrogen. After stirring for min, (12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene (200 mg, 0.52 mmol, 1.00 equiv) was added and the resulting solution was stirred overnight at room temperature for 8 h. The reaction was then quenched with saturated aqueous NH4Cl and extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (4:1) to afford 4-[[(12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]-N,N-dimethylcyclohexan-1-amine (110 mg, 43%) as a light yellow solid. MS (ES): m/z 490 (M+H)+.