Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][C:17]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[CH:18][CH:19]=3)=[N:8][C:7]=2[NH:6][C:5]1=O)[CH2:2][CH3:3].O=P(Cl)(Cl)[Cl:35].[NH4+].[Cl-]>>[Cl:35][C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][C:17]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[CH:18][CH:19]=3)=[N:8][C:7]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1c(=O)[nH]c2nc(-c3ccc(NCc4cccc(C(F)(F)F)c4)nc3)[nH]c2c1=O
Agent: [Cl-]
Agent: [NH4+]
Product: CCCn1c(Cl)nc2nc(-c3ccc(NCc4cccc(C(F)(F)F)c4)nc3)[nH]c2c1=O
Temperature: 127.5 °C
Yield: 26 %

Procedure:
A mixture of 1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-3,7-dihydro-purine-2,6-dione (0.2 g, 0.45 mmol), POCl3 (5 ml) and NH4Cl (0.486 g, 9 mmol) were heated at 125-130° C. for 20 hours. Reaction mixture was cooled to 20-25° C. It was then concentrated under vacuum. The residue was dissolved in water (50 ml) and precipitated solid was filtered off. The solid obtained was further purified by column chromatography to obtain pure 2-Chloro-1-propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one as pale yellow solid (0.054 g, 26%).
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][CH2:4]CC(=O)C([O-])=O.CC(CCC=C(C)C)[CH2:19][CH2:20][CH:21]([CH3:27])[C:22](=[O:26])[C:23]([O-:25])=[O:24]>>[CH3:27][CH:21]([CH2:20][CH3:19])[C:22](=[O:26])[C:23]([O:25][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])=[O:24]
Reactant: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Reactant: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Product: CCC(C)C(=O)C(=O)OCCC(C)CCC=C(C)C

Procedure:
MS (EI): 268 (M+, 1); 250 (1); 240 (1); 207 (1); 183 (2); 155 (2); 138 (10); 123 (14); 109 (7); 95 (18); 85 (32); 81 (26); 69 (51); 57 (100); 41 (53); 29 (18).
Reaction SMILES: C(OC(=O)[NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:13](=[O:24])[C:14]([Br:23])=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)[N:16]=[C:7]12)C.Br>C(O)(=O)C>[NH2:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:13](=[O:24])[C:14]([Br:23])=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)[N:16]=[C:7]12
Reactant: CCOC(=O)NC1CCCCn2c1nc(-c1ccncn1)c(Br)c2=O
Agent: Br
Solvent: CC(=O)O
Product: NC1CCCCn2c1nc(-c1ccncn1)c(Br)c2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a solution of 0.34 g (0.84 mmol) of (+/−)(3-bromo-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-yl)-carbamic acid ethyl ester in 2 mL of acetic acid was added 0.78 mL (4.21 mmol) of a solution of hydrobromic acid (5.7N in acetic acid). The reaction was stirred at 100° C. for 3 h. The solvent was evaporated and an acid-basic work-up gave 65 mg (33%) of 10-amino-3-bromo-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one as an orange oil. The compound was used as such in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1>C(N(CC)CC)C.[Pd].CCO>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[C:4]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:16][CH:17]=1)=[CH:3][CH:2]=[N:7]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccnn3ccnc23)cc1
Reaction time: 12 h
Yield: 93.3 %

Procedure:
To a mixture of tert-butyl 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)phenylcarbamate (0.1 g, 0.28 mmol) from 1a and EtOH (4 mL) in a 500 ml PARR bottle was added 10% Pd/C (0.02 g) and 2 drops of triethyl amine. The PARR bottle was then charged with H2 at 55 psi and allow to shake at room temperature for 12 hours. The reaction mixture was then filtered and the filtrate concentrated in vacuo to give 0.085 g of crude tert-butyl 4-(imidazo[1,2-b]pyridazin-8-ylamino)phenylcarbamate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[C:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:26]>>[Cl:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][C:25]#[N:26])=[CH:29][CH:30]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:23])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: N#CCc1ccc(B(O)O)cc1
Product: CC(c1ccc(-c2ccc(CC#N)cc2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 165, step 3) was reacted with 4-cyanomethylphenylboronic acid to give the title compound as an off-white solid. MS (m/e)=461.3 [M+H+].
Reaction SMILES: [N:1]1([C:7](OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][CH:15]([O:17][C:18](=[O:41])[NH:19][C@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[S:31][C:32](C=O)=[CH:33][N:34]=3)[CH:28]=2)[N:23]([C:37](=[O:39])[CH3:38])[C@@H:22]([CH3:40])[CH2:21]1)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>ClCCl>[C:37]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([C:30]3[S:31][C:32]([CH2:7][N:1]4[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]4)=[CH:33][N:34]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:19][C:18](=[O:41])[O:17][CH:15]([CH3:14])[CH3:16])[CH2:21][C@@H:22]1[CH3:40])(=[O:39])[CH3:38]
Reactant: CC(=O)N1c2ccc(-c3ncc(C=O)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1c2ccc(-c3ncc(CN4CCNCC4)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
1,1-Dimethylethyl 1-piperazinecarboxylate (48.2 mg, 0.259 mmol), 1-methylethyl[(2S,4R)-1-acetyl-6-(5-formyl-1,3-thiazol-2-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 106) (104 mg, 0.259 mmol) and sodium triacetoxyborohydride (220 mg, 1.036 mmol) were dissolved in dichloromethane (DCM) (4 mL) and the resulting mixture was stirred at room temperature under nitrogen for 16 h before being treated with a saturated NaHCO3 aqueous solution. The two layers were separated using a phase separator cartridge and the organic phase was concentrated in vacuo. The residue was loaded on a 20 G SCX cartridge which was eluted with MeOH then with a 2M NH3 solution in MeOH. The ammonia fractions were concentrated in vacuo to give a residue which was dissolved in DCM (3 mL) and treated with TFA (0.5 mL, 6.49 mmol). After 1 h, the mixture was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 1 to 10% (2M NH3 in MeOH) in DCM) gave 1-methylethyl {(2S,4R)-1-acetyl-2-methyl-6-[5-(1-piperazinyl methyl)-1,3-thiazol-2-yl]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (70 mg, 0.148 mmol, 57.3% yield).
Reaction SMILES: [H-].[Na+].C(OC(=O)[NH:9][CH2:10][CH2:11][SH:12])(C)(C)C.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>O1CCCC1.C(Cl)Cl>[F:14][C:15]1[N:16]=[C:17]([S:12][CH2:11][CH2:10][NH2:9])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NCCSc1cccc(F)n1
Temperature: 0 °C
Yield: 127.6 %

Procedure:
Suspend sodium hydride (138 mg, 5.46 mmol) in tetrahydrofuran (6 mL) and cool to 0° C. in an ice bath. Add (2-mercaptoethyl)carbamic acid tert-butyl ester (0.461 mL, 2.73 mmol) dropwise over 5 minutes. Stir reaction for 30 minutes, add 2,6-difluoropyridine (0.495 mL, 0.546 mmol), remove ice bath and stir an additional hour. Re-cool reaction and quench with water. Extract with 1/1 hexanes/ethyl acetate. Dry organics over magnesium sulfate, filter and evaporate. Perform flash column chromatography (ethyl acetate/hexanes). Dissolve resulting orange oil in trifluoroacetic acid (3 mL) and stir for 15 minutes. Concentrate the reaction with a stream of dry nitrogen, re-dissolve in dry methylene chloride and evaporate to give 120 mg of the title compound as an orange oil. 1H NMR (d MeOH): 7.70 (m, 1H), 7.22 (m, 1H), 6.78 (m, 1H), 3.44 (m, 2H), 3.34 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:17]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:27]([CH3:29])[CH3:28])[S:14]3)[C@H:10]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[Na+].O>[CH3:29][N:27]([CH3:28])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([CH2:18][OH:19])[C@@H:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=3)[C@H:10]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[C@H:11]2[N:12]=1
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Yield: 90.7 %

Procedure:
(3aR,5R,6S,7R,7aR)-6,7-bis(4-methoxybenzyloxy)-5-((tert-butyldimethylsilyloxy)methyl)-N,N-dimethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-amine (9.5 g, 15.8 mmol) in THF (100 mL) was treated with TBAF (8.27 g, 31.6 mmol) overnight at room temperature. The resulting solution was diluted with brine (200 mL), extracted with ethyl acetate (2×200 mL), and dried over anhydrous magnesium sulfate. After removal of solvents, the residue was purified by silica gel column, eluted with 1-2.5% MeOH in dichloromethane to give compound 10 as a yellow oil (7.0 g, 86%). (ES, m/z): [M+H]+ 489.0; 1H NMR (300 MHz, CDCl3) δ 7.32-7.62 (m, 2H), 7.22-7.28 (m, 2H), 6.85-6.91 (m, 4H), 6.26-6.28 (d, J=6.6 Hz, 1H), 4.52-4.73 (m, 4H), 4.31-4.34 (d, J=11.4 Hz, 1H), 4.23 (s, 1H), 181 (s, 6H), 3.53-3.76 (m, 4H), 3.01 (m, 6H), 1.78-1.82 (m, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:22][CH:23]=[CH2:24])[CH2:20][OH:21])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:22][CH:23]=[CH2:24])[CH:20]=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: C=CC[C@H](CO)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CC[C@H](C=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 100.1 %

Procedure:
To a solution of oxalyl chloride (0.713 mL, 8.24 mmol) at −78° C. in dry methylene chloride (100 mL) under nitrogen in a three necked flask was added dropwise a solution of DMSO (1.37 mL, 19.8 mmol) in methylene chloride (4 mL) with stirring at −78° C. for an additional 20 min. A solution of (2S)-2-(3,4-dichlorophenyl)pent-4-en-1-ol (1.26 g, 5.45 mmol) in methylene chloride (50 mL) was added dropwise (45 min) while maintaining the reaction temperature below −60° C. After stirring at −60° C. for an additional 2 h, triethylamine (4.6 mL, 33.3 mmol) was added dropwise. The stirred reaction mixture was allowed to warm to ambient temperature for 2 h, cooled in ice, quenched by addition of water (80 mL), and stirred for an additional 30 min. The organic layer was washed with water and brine, dried (Na2SO4), and evaporated to give 1.25 g of the title compound which was used without further purification. This material was determined to be about 72% pure by HPLC.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=O.C(NC(C)C)(C)C.C([Li])CCC.[O:35]1CC[CH2:37][CH2:36]1>CCCCCC.C(N=CC)(C)(C)C>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:37][CH:36]=[O:35])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: CC=NC(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=CC=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 3,3'-bis(trifluoromethyl)benzophenone (31.8 g), diisopropylamine (32.2 mL), 1.6M n-butyl lithium in hexane (144 mL), acetaldehyde N-tert-butylimine (14.75 mL) diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). After the usual work up, the product was purified by HPLC to give 30,8 g of 3,3-bis[3-(trifluoromethyl)phenyl]-2-propenal as an oil.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:38])[C:29]3[N:33]=[C:32]([CH2:34][O:35][CH3:36])[NH:31][C:30]=3[CH:37]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][O:35][CH2:34][C:32]1[NH:31][C:30]2[CH:37]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:38])[C:29]=2[N:33]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: COCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1

Procedure:
49 mg (0.19 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 50 mg (0.16 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(methoxymethyl)-4-methyl-1H-benzo-[d]imidazole and 0.10 mL (0.57 mmol) DIPEA in 2.0 mL DMF were stirred at 40° C. over the weekend. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:5][CH:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC2CCCCC2C(NC(=O)C(F)(F)F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C2CCCCC2C1
Yield: 88.2 %

Procedure:
A solution of tert-butyl 4-[(trifluoroacetyl)amino]octahydroisoquinoline-2(1H)-carboxylate (1.75 g) and 20% aqueous potassium carbonate solution (10 ml) in methanol (25 ml) was stirred at 60° C. for 15 hr. The solvent was evaporated under reduced pressure, saturated brine (20 ml) was added to the residue, and the mixture was extracted with chloroform (30 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (1.12 g) as an oil.
Reaction SMILES: O[C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18]C=O)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:10][C:4]1([CH3:11])[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[CH:3]1
Reactant: CC1(C)CC(C)(C)CC(O)(c2ccccc2NC=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)C=C(c2ccccc2N)CC(C)(C)C1
Temperature: 110 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of N-[2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)phenyl]formamide (4.00 g, 14.5 mmol) in toluene (40 mL) was added pyridinium p-toluenesulfonate (365 mg, 1.45 mmol), followed by stirring at 110° C. for 1 hour. Then, the reaction mixture was cooled down to 50° C., methanol (40 mL) and a 5N aqueous solution of sodium hydroxide (14.5 mL) were added thereto, and the reaction mixture was stirred at 80° C. for 14 hours. The reaction mixture was allowed to cool down to room temperature, the aqueous layer was removed. The organic layer was washed with water and a 5% aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 3.33 g of the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:16]=[C:17]([N+:21]([O-])=O)[CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[OH-].[NH4+]>B#[Ni].CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[NH2:21])=[CH:10][CH:9]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)c2ccc(Cc3cccc([N+](=O)[O-])c3)n2C)cc1
Agent: B#[Ni]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(C(=O)c2ccc(Cc3cccc(N)c3)n2C)cc1
Temperature: 65 °C
Yield: 92.2 %

Procedure:
A mixture of 3-{5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-ylmethyl}-nitrobenzene (0.86 g, 2.6 mmol) [prepared as in Example 8, Step (c)], nickel boride (1.0 g), 10% HCl (13 ml), and methanol (35 ml) was heated at 65° C. for 40 min. The reaction mixture was cooled to room temperature, made basic with concentrated ammonium hydroxide, and filtered through Celite®. The product was extracted into ethyl acetate, and the organic extracts were washed with water and brine, and dried over sodium sulfate. Evaporation of the organics gave 3-{5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-yl-methyl}aniline (0.73 g, 99%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[C:22]([CH2:26][CH2:27][O:28]C(=O)C)[CH:23]=[CH:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[CH:12]([CH3:32])[N:11]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:10]2=[O:41])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:28][CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([NH:19][C:16]2[N:15]=[C:14]3[N:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]#[N:2])[C:10](=[O:41])[N:11]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH:12]([CH3:32])[C:13]3=[CH:18][N:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOC(C)=O)c4)ncc3C2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCO)c4)ncc3C2C)cc1

Procedure:
Acetic acid (±)-2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl ester (10 g; 1.81 mmol) (from Example 3c supra) was dissolved in a mixture of methanol (17 mL) and water (7 mL) and treated with potassium carbonate (1.00 g; 7.26 mmol) at room temperature for 19 hours. The reaction mixture was partitioned between ethyl acetate and water-brine mixture. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (Biotage 40M; ethyl acetate) to give (±)-3-[7-[3-(2-hydroxy-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile. (Yield 0.67 g; 72.9%). A small amount of additional material bumped over into the solvent trap during concentration. This material was recovered and crystallized from ethyl acetate. (Yield 0.09 g; 9.9%). Melting Point: 195–200° C. HR-MS(ES+) m/z Calculated for C29H26N6O3 ([M+H]+): 507.2139. Found: 507.2145. HR-MS(ES+) m/z Calculated for C29H26N6O3 ([M+Na]+): 529.9158. Found: 529.1963.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][C:25]=2[CH:32]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>>[CH2:1]([C:3]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][C:25]=2[CH:32]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[OH:19])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OC2CCCCC2=O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OC2CCCCC2O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Yield: 65 %

Procedure:
5-{1-Ethyl-1-[3-methyl-4-(2-oxo-cyclohexyloxy)-phenyl]-propyl}-benzofuran-2-carboxylic acid (357 mg, 0.822 mmol) (Example N) was reacted with sodium borohydride (68 mg, 1.6 mmol) in an analogous manner to Example 31 to yield (13 mg, 65% yield).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.ClCCl>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][S:12]([C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:2]([F:1])=[CH:3][CH:4]=2)(=[O:14])=[O:13])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)c2c1CCCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluoro-5,6,7,8-tetrahydro-naphthalene-1-sulfonyl chloride (860 mg, 3.46 mmol) was dissolved in THF (10 mL). Triethylamine (350 mg, 0.49 mg, 3.46 mmol) was added, followed by 4-amino-piperidine-1-carboxylic acid tert-butyl ester (694 mg, 3.46 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was diluted with dichloromethane (50 mnL) and charged to a separatory funnel. The organic layer was washed with water and brine, then dried over MgSO4. Filtration and concentration in vacuo afforded a yellow foam. Wt.: 1.35 g (95%). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, 1H), 6.95 (t, 1H), 4.47 (d, 1H), 3.93 (m, 2H), 3.27 (m, 1H), 3.11 (m, 2H), 2.76 (m, 4H), 1.81 (m, 6H), 1.44 (s, 9H), 1.32 (m, 2H); LC/MS m/z 411 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)([O-])=O.CCO.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:16]([N:13]1[CH2:12][CH2:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added 1-(2-nitrophenyl)-4-benzylpiperazine (42 g, 160 mmol), EtOH (300 mL), and SnCl2.2H2O (Aldrich) (141 g, 624 mmol), and the reaction mixture was warmed to 60° C. for 5 h. The reaction mixture was treated with 1N NaOH (30 mL) and CH2Cl2. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). All organic fractions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the amine as a light yellow oil (34 g). MS (ESI, pos. Ion) m/z: 268 (M+H); MS (ESI, neg. Ion) m/z: 266 (M−H). Calc'd for C17H21N3: 267.17.