Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1/[CH:4]=[C:20](/[N+:17]([O-:19])=[O:18])\[CH3:21]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1c(Cl)cc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: C/C(=C\c1c(Cl)cc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
To a stirred solution of 2,4,6-trichloro-benzaldehyde (19 g, 90.69 mmol) and ammonium acetate (16.75 g, 217 mmol) in acetic acid (76 ml, 4 Vol.), nitroethane (45.1 ml, 625 mmol) was added in drops at a temperature of 0° C. The reaction mass was stirred at a temperature of 100° C. for 90 minutes. When the TLC confirmed the completion of the reaction, the reaction mass was allowed to attain ambient temperature and was diluted with ice cold water (700 ml), further aqueous layer was then extracted with ethyl acetate (3×50 ml). Combined ethyl acetate layer was washed with saturated sodium bicarbonate solution to neutral pH, then with water, followed by brine wash and dried under anhydrous Na2SO4 before the complete evaporation of solvents. The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 1% ethyl acetate in hexane as elution system to give 1,3,5-trichloro-2-((E)-2-nitro-propenyl)-benzene (15 g, 61%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:23]([O-])=O)=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H]>CO.[Pt]>[NH2:23][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[C:13]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:12]=1
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Yield: 80 %

Procedure:
A suspension of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (3.89 g, 10 mmol) in methanol (80 ml) containing 10% platinum on activated carbon (50% wet) (389 mg) was hydrogenated at 1.8 atmospheres pressure until uptake of hydrogen ceased. The mixture was filtered and the volatiles were removed by evaporation. The residue was dissolved in water (30 ml) and adjusted to pH10 with a saturated solution of sodium hydrogen carbonate. The mixture was diluted with ethyl acetate/ether (1/1) and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate/ether and the organic layers were combined. The organic layers were washed with water, brine, dried (MgSO4), filtered and the volatiles were removed by evaporation. The resulting solid was triturated in a mixture of ether/petroleum ether, filtered, washed with petroleum ether and dried under vacuum at 60° C. to give ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (2.58 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[N:4]=[CH:3]1.[CH3:11][N:12]=[C:13]=[S:14]>C(#N)C>[CH3:1][N:2]1[C:6]2[CH2:7][N:8]([C:13](=[S:14])[NH:12][CH3:11])[CH2:9][CH2:10][C:5]=2[N:4]=[CH:3]1
Reactant: CN=C=S
Reactant: Cn1cnc2c1CNCC2
Solvent: CC#N
Product: CNC(=S)N1CCc2ncn(C)c2C1

Procedure:
A solution of 1 g of 3-methyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1 g of methyl isothiocyanate in 10 ml of acetonitrile is refluxed for 4 h. The solution is cooled and filtered: 0.9 g of 3-methyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 235°, are collected.
Reaction SMILES: [OH: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][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O: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][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(CCCCCCCCCCCCO)C(C)(C)CCC1
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCCCCCCCC1=C(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 1-(12-hydroxydodecyl)-2,6,6-trimethyl-1-cyclohexene (316 mg, 1.026 mmol) were added acetic anhydride (7 ml) and pyridine (7 ml). The mixture was stirred at room temperature for 1 hour, then quenched with HCl 5%, extracted with ether, washed with water, dried with MgSO4 and concentrated in vacuo to obtain 1-(12-acetoxydodecyl)-2,6,6-trimethyl-1-cyclohexene as a colorless oil (353 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.[CH:36](=O)[CH3:37].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:36][CH3:37])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: CC=O
Reactant: COc1ccc(CNCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(OC)cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(4-methoxybenzylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.5 g) as starting compound, acetaldehyde (0.22 ml) and sodium cyanoborohydride (0.24 g) were reacted and treated in the same manner as in Example 136 to give 0.8 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-methoxybenzyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:23][CH2:20][CH2:21][CH3:22])[N:11]=1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: CCCN
Product: CCCNc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 203 mg (3.43 mmol) of n-propylamine to give 12 mg (12% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14][OH:15].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(O)(O)=O>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH2:14][OH:15])[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1cccc2nc(CO)c(Br)c(=O)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: O
Solvent: CC#N
Product: Cc1cccc2nc(CO)c(-c3cccc(F)c3)c(=O)n12
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.09450 g, 0.3512 mmol), 3-fluorophenylboronic acid (0.09827 g, 0.7024 mmol), tetrakis(triphenylphosphine)palladium (0.02029 g, 0.01756 mmol), and sodium carbonate anhydrous (0.1861 g, 1.756 mmol) in acetonitrile-water (3:1) (4 mL) was stirred at 85° C. After 2 h, the mixture was cooled to rt and partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 20 min as eluent to give 3-(3-fluorophenyl)-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid: Mass Spectrum (ESI) m/e=285.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@:8]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CCCCCC=CC[C@H]1c2ccc(OC)cc2SC[C@@]1(C)c1ccc(OC)cc1)CCCC(F)(F)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCCCC[C@H]1c2ccc(OC)cc2SC[C@@]1(C)c1ccc(OC)cc1)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 93.1 %

Procedure:
10% Pd/C (1.04 g) was added to a solution of the ethyl 10-[(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)-8-decenoate (3.46 g, 5.268 mmol) in tetrahydrofuran (60 ml) followed by stirring for 23 hours at room temperature under a hydrogen stream. After the reaction mixture was filtered, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to give ethyl 10-[(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate (3.23 g, Yield 93%) as an oil.
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:54]=[CH:53][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:52][C:47]1[CH:46]=[C:45]([CH:50]=[C:49]([F:51])[CH:48]=1)[CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=3)=[CH:54][CH:53]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4cc(F)cc(F)c4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1cc(F)cc(F)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 47.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(3,5-difluorobenzyl)-1-piperidinecarboxamide (0.165 g, 0.20 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.05 g, 0.095 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][CH2:28]C)=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:32](N)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][NH:26][CH:27]([CH3:28])[CH3:32])=[CH:23][CH:24]=3)=[CH:30][CH:31]=2)=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: CCCNCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1
Product: CC(C)NCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1

Procedure:
Compound 4 was synthesized using the procedure described for Compound 2 except that isopropylamine was used in the last reductive amination step. Compound 4 was obtained as a yellow gum. MS 433; 1H NMR (CDCl3) δ 4.10 (t, 2H), 3.86 (d, 2H, becomes singlet with D2O exchange), 2.80 (m, 1H), 1.09 (d, 6H).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])C.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])[CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)C1CNc2ccccc2O1
Reactant: CCCCN
Product: CCCCNC(=O)C1CNc2ccccc2O1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 600 mg of 2(R,S)-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine (Example 16)) and 1.2 ml of butylamine is stirred at 60° C. for 1 h. The reaction mixture is concentrated and the residue is purified directly by means of FC over 50 g of silica gel with a 20:1 mixture of methylene chloride and diethyl ether as the mobile phase. 2(R,S)-Butylaminocarbonyl-3,4-dihydro-2H-1,4-benzoxazine is obtained: Rf (20:1-mixture of methylene chloride and diethyl ether)=0.32.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([CH3:39])[N:33]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[C:32]2=[O:48]>CN(C=O)C>[O:47]=[C:41]1[CH:40]([N:33]2[C:32](=[O:48])[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([CH2:28][NH:27][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=4)[CH:30]=3)[N:35]=[C:34]2[CH3:39])[CH2:45][CH2:44][C:43](=[O:46])[NH:42]1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNC(=O)c3cccc(C(F)(F)F)c3)cc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a stirred solution of 3-trifluoromethyl-benzoic acid (0.30 g, 1.6 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′ carbonyldiimidazole (0.28 g, 1.7 mmol), and the mixture was stirred for one hour. Then 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-trifluoromethyl-benzamide as an off-white solid (430 mg, 59% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% F3PO4, grad. to 95/5 in 5 min, kept 5 min. 6.20 min (98.5%); mp, 220-222° C.; 1HNMR (DMSO-d6) δ 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH3), 4.62 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.59-8.25 (m, 7H, Ar), 9.42 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.90, 23.41, 30.60, 42.45, 56.53, 120.02, 123.79 (q, JC-F=11 Hz), 123.79 (d, JC-F=3 Hz), 123.95 (q, JC-F=275 Hz), 124.04, 126.67, 127.96 (d, JC-F=3 Hz), 129.19 (d, JC-F=32 Hz), 129.74, 131.38, 134.18, 134.88, 137.81, 145.88, 154.65, 160.43, 164.73, 169.45, 172.59. LCMS MH=473; Anal Calcd For C23H19N4O4F3+0.3H2O: C, 57.81; H, 4.13; N, 11.73; F, 11.93. Found: C, 57.77; H, 4.11; N, 11.69; F, 11.97.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH:10]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:19][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NC1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Nc1nc(Cl)cc(NC2CCc3ccccc32)n1
Temperature: 160 °C
Yield: 86.9 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (500 mg, 3.09 mmol), 2,3-dihydro-1H-inden-1-amine (500 mg, 3.78 mmol) and triethylamine (2 mL) in NMP (3 mL) was heated to 160° C. for 2 hours in a BiotageInitiator® microwave synthesizer. The reaction mixture was evaporated and purified by SiO2 chromatography eluting with 1:3 petroleum ether/THF to afford the title compound (700 mg) as a yellow solid. LC-MS (ES) m/z=261 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[C:26](OC(=O)C)(=O)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[N:19]=[C:26]2[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c(N)c1OC
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2ncnc3c2c(c1OC)N=C(C)N3c1cccc(Cl)c1

Procedure:
A solution of N4-(3-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (0.2 g, 0.60 mmol) (from Example 11, Step B supra) in acetic anhydride (3 mL) was heated at 150° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was extracted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 3-(3-chloro-phenyl)-8,9-dimethoxy-2-methyl-3H-1,3,4,6-tetraaza-phenalene as a yellow solid. (Yield 90 mg, 42%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:26])[CH2:17][C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]([Cl:25])[CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([CH:16]([OH:26])[CH2:17][C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]([Cl:25])[CH:19]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (240 mg) is added to an ice-cooled solution of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylic acid tert-butyl ester (1.65 g) in a mixture of tetrahydrofuran (40 mL) and water (10 mL). The resulting mixture is stirred for 0.5 h at room temperature. 2 N Aqueous citric acid is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 65:35) to give the title compound. LC (method 3): tR=1.48 min; Mass spectrum (ESI+): m/z=419, 421 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.O=S(Cl)[Cl:16].O>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[Cl:16][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: O
Product: FC1(F)Oc2ccc(CCl)cc2O1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
(2,2-difluoro-1,3-benzodioxol-5-yl)-methanol (1.0 eq) is dissolved in MTBE (5 vol). A catalytic amount of DMAP (1 mol %) is added and SOCl2 (1.2 eq) is added via addition funnel. The SOCl2 is added at a rate to maintain the temperature in the reactor at 15-25° C. The temperature is increased to 30° C. for 1 hour then cooled to 20° C. then water (4 vol) is added via addition funnel maintaining the temperature at less than 30° C. After stirring for an additional 30 minutes, the layers are allowed to separate. The organic layer is stirred and 10% (w/v) aq. NaOH (4.4 vol) is added. After stirring for 15 to 20 minutes, the layers are allowed to separate. The organic phase is then dried (Na2SO4), filtered, and concentrated to afford crude 5-chloromethyl-2,2-difluoro-1,3-benzodioxole that is used directly in the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=1[CH2:32][C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[CH:37]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=1[CH2:32][C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[C:37]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Reactant: Cc1cc(Cc2ccccc2Br)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C(C)C
Yield: 49.2 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (0.983 g, 4.16 mmol, RN-117439-59-5), oxalyl chloride (0.398 mL, 4.56 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.535 mL, 4.58 mmol) and 2-(2-bromo-benzyl)-4,5-dimethyl-furan (1.10 g, 4.16 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 0.990 g (49%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.15 (d, 12H), 1.84 (s, 3H), 2.18 (s, 3H), 3.27 (septet, 2H), 3.73 (s, 3H), 3.91 (s, 2H), 7.12-7.16 (m, 2H), 7.29 (t, 1H, 7.44 (s, 2H), 7.50 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[Br:1][C:2]1[S:6][C:5]([CH2:7][NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: CC(C)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1ccc(Br)s1

Procedure:
In analogy to example 13, step 1, 5-bromothiophene-2-carboxaldehyde was reacted with isobutylamine and sodium borohydride in methanol to give (5-bromo-thiophen-2-ylmethyl)-isobutyl-amine as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccccc1/C=C/C(=O)O
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1ccccc1/C=C/C(=O)Nc1cnn(Cc2ccc(C(C)=O)o2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-methoxy-phenyl)-acrylic acid.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2nnnn2C)s1
Agent: Cl
Solvent: CCO
Product: Cn1nnnc1Sc1cnc(N)s1
Yield: 48.4 %

Procedure:
A mixture of 2-acetylamino-5-(1-methyl-1H-tetrazol-5-ylthio)thiazole (2.0 g) in a mixture of ethanol (20 ml) and aqueous 6N-hydrochloric acid (5 ml) was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was adjusted to pH 8 using aqueous sodium bicarbonate under ice cooling. The precipitates were collected by filtration, washed with water and the solid was recrystallized from ethanol to give 2-amino-5-(1-methyl-1H-tetrazol-5-ylthio)thiazole (0.81 g, yield: 48.5%). mp: 186°-188° C. (dec.)
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>C(O)(C)C>[CH:17]([NH:20][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1)([CH3:19])[CH3:18]
Reactant: Clc1ncnc2occ(-c3ccccc3)c12
Reactant: CC(C)N
Solvent: CC(C)O
Product: CC(C)Nc1ncnc2occ(-c3ccccc3)c12
Reaction time: 20 h

Procedure:
Into a 50 mL round bottom flask was placed 4-chloro-5-phenylfuro[2,3-d]pyrimidine, isopropanol (25 mL), and isopropylamine (1.5 g, 25 mmol). The flask was equipped with a magnetic stir bar, a reflux condenser, and argon balloon and the reaction was brought to reflux with stirring for 20 hours.