Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.[CH2:18]=O.C[O-].[Na+].[BH4-].[Na+]>CO.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:18][NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:7]=1
Reactant: COc1ccc(N)cc1NC(=O)OC(C)(C)C
Reactant: C=O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1ccc(OC)c(NC(=O)OC(C)(C)C)c1
Temperature: 50 °C
Yield: 104.7 %

Procedure:
A suspension of 1,1-dimethylethyl [5-amino-2-(methyloxy)phenyl]carbamate (1.94 g, 8.14 mmol), paraformaldehyde (1.222 g, 40.7 mmol), and sodium methoxide (2.199 g, 40.7 mmol) in methanol (50 ml) was maintained at 50° C. for 16 hours, cooled, sodium borohydride (0.924 g, 24.42 mmol) was added portionwise, and the solution was re-heated to 50° C. and maintained for an additional 24 hours. The solution was cooled, diluted with ethyl acetate, saturated sodium bicarbonate, and the organic layer was dried over sodium sulfated, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 1,1-dimethylethyl [5-(methylamino)-2-(methyloxy)phenyl]carbamate (2.15 g, 8.52 mmol, quant. Yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (s, 1 H), 7.10 (d, J=1.6 Hz, 1 H), 6.76 (d, J=8.8 Hz, 1 H), 6.14 (dd, J=8.7, 2.7 Hz, 1H), 5.07-5.31 (m, 1 H), 3.61-3.74 (m, 3 H), 2.60 (d, J=4.4 Hz, 3 H), 1.44 (s, 9 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[C:20]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=c1ccn(COCCO)c(=O)[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=c1ccn(COCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Yield: 20 %

Procedure:
1-(2-hydroxy-ethoxymethyl)uracil (0.50 g, 2.69 mmol) and triphenylmethyl chloride (0.82 g, 2.96 mmol) were stirred in dry pyridine (20 ml) overnight at 50° C. under an atmosphere of nitrogen. H2O (10 ml) was added and the mixture was extracted with CHCl3 (2×50 ml), dried (Na2SO4) and reduced in vacuo to obtain a crude product, which was purified by column chromatography eluting with 0→3% MeOH/CHCl3 to obtain the title compound as a white solid (0.23 g, 20%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>CC(C)=O>[O:23]=[C:21]([CH3:22])[CH2:20][O:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][C:4](=[O:12])[CH:3]=1
Reactant: CC(=O)CCl
Reactant: O=c1cc(O)c2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc(=O)oc2ccccc12
Temperature: 0 °C
Yield: 58.7 %

Procedure:
To a solution of 4-hydroxycoumarin (1.62 g, 10 mmol) in acetone (20 ml) were added potassium carbonate (5.53 g, 40 mmol) and chloroacetone (1.38 g, 15 mmol). The resulting mixture was refluxed for 4 h. (monitored by TLC). Evaporation of the solvent gave a residue which was poured into ice water (50 ml). The resulting solid was collected and crystallized from ethyl acetate to afford 4-(2-Oxopropoxy)-2H-1-benzopyran-2-one (1a) (1.28 g, 55.1%) as a white needle crystal. mp: 163°-165° C.; IR(KBr) νmax : 1716, 1625; UV(CHCl3) λmax (log ε): 305 (3.83), 266 (4.05); 1H-NMR (CDCl3): δ2.36 (s, 3H, CH3), 4.77 (s, 2H, OCH2), 5.57 (s, 1H, 3-H), 7.28-7.36 (m, 2H, 6- and 8-H), 7.54-7.63 (m, 1H, 7-H), 7.88-7.94 (m, 1H, 5-H). Anal. Calcd for C12H10O4 : C, 66.05; H, 4.62. Found: C, 66.01; H, 4.64.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1>>[CH3:22][O:21][C:18]1[N:19]=[CH:20][C:15]([NH:14][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cn1
Yield: 68 %

Procedure:
The title compound (1.05 g, 3.4 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (1.1 g, 5.0 mmol) and 5-amino-2-methoxypyridine (683 mg, 5.5 mmol) using the methods of (IntA1), step 1.
Reaction SMILES: [C:1]([N:8]([CH3:29])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH3:25])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[C:34]#[N:35]>>[C:34]([C:33]1[CH:32]=[C:31]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH3:25])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:29])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)[CH:38]=[CH:37][CH:36]=1)#[N:35]
Reactant: N#Cc1cccc(Br)c1
Reactant: CCOc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 11 (374 mg, 0.92 mmol) is coupled to 3-bromobenzonitrile (200 mg, 1.10 mmol) using Method B to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[F:14][C:15]([F:32])([F:31])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25]3)=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[F:32][C:15]([F:14])([F:31])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:26][CH2:25]3)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 25 °C

Procedure:
1.25 g of commercially available 4-cyano-benzenesulfonyl chloride were dissolved in 35 ml dichloromethane. Then 760 mg 5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole hydrochloride were added followed by 2.14 ml triethylamine. The mixture was stirred at room temperature for fifteen minutes. Then 100 ml of dichloromethane were added, the mixture washed with 40 ml water and brine and then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 517 mg of 4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile as amorphous lyophilisate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:19][CH:18]3[CH:14]([CH2:15][NH:16][CH2:17]3)[CH2:13]1)[N:6]=[CH:5]2.[F:20][C:21]1[C:22]([C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[F:20][C:21]1[C:22]([C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:35]=2)=[C:23]([C:24]([N:16]2[CH2:17][CH:18]3[CH:14]([CH2:13][N:12]([C:7]4[N:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[N:8]=4)[CH2:19]3)[CH2:15]2)=[O:25])[CH:27]=[CH:28][CH:29]=1
Reactant: Fc1ccc2nc(N3CC4CNCC4C3)ncc2c1
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Product: O=C(c1cccc(F)c1-c1ncccn1)N1CC2CN(c3ncc4cc(F)ccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 43 and 3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI): mass calculated for C25H20F2N6O, 458.17; m/z found 459.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.98 (d, J=8.1, 1H), 8.82-8.74 (m, 2H), 7.61 (dt, J=12.7, 6.4, 1H), 7.53-7.41 (m, 2H), 7.31 (td, J=8.0, 2.7, 1H), 7.25-7.18 (m, 2H), 7.15 (t, J=4.9, 1H), 4.00-3.88 (m, 1H), 3.89-3.69 (m, 3H), 3.68-3.52 (m, 3H), 3.36 (dd, J=10.9, 4.6, 1H), 3.14-2.97 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=[CH:11]2.[OH-].[Na+]>CCOCC>[CH3:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH2:18][OH:19])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cc(C(=O)O)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc2cc(CO)ccc2c1

Procedure:
To a suspension of 2.7 g. of lithium aluminum hydride in 75 ml. of dry ether is added dropwise a solution containing 5.5 g. of 6-methyl-2-naphthoic acid in 75 ml. of dry ether. The mixture is refluxed for three hours, cooled, and treated with 10% sodium hydroxide solution. The mixture is then filtered and dried to yield 6-methyl-2-naphthalenemethanol.
Reaction SMILES: C(OC([N:11]1[C@H:20]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][C@H:18]2[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:24]([NH:23][C:21]([C@@H:20]1[CH2:19][C@H:18]2[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][NH:11]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Yield: 100 %

Procedure:
A solution of 0.689 g (1.85 mmol) of 2-(benzyloxy-carbonyl)-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 20 ml of ethanol was hydrogenated in the presence of 0.01 g of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 18 hours. The catalyst was removed by filtration and the solvent was removed by evaporation to give 1.85 mmol of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a clear oil: MS: m/e 239 [M+H]+, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[NH:46][C:47](OC1C=CC([N+]([O-])=O)=CC=1)=[O:48])[C:39]([O:41][CH3:42])=[O:40]>C(N(CC)CC)C.C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:47]([NH:46][C:45]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=2[O:35][CH3:34])=[O:48])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(OC)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 150 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate in 0.140 mL of triethylamine and 3.0 mL of THF was added 155 mg of methyl 3-methoxy-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate prepared in the same manner as in Production Example 11, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}amino)-3-methoxybenzoate as a crude product (yellow foamy substance, 297 mg). ESI+: 652
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].Cl[C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1>O1CCCC1>[F:3][C:4]([F:12])([F:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: OCCCCCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)CCCCCOc1nsnc1-c1cccnc1
Yield: 31 %

Procedure:
To a mixture of sodium hydride (12.8 mmol) and 6,6,6-trifluoro-1-hexanol (3.0 g, 19.2 mmol) in tetrahydrofuran (40 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)-pyridine (1.3 g, 6.4 mmol). The mixture was refluxed for 36 h and evaporated. After evaporation the residue was dissolved in water then extracted with diethyl ether. The dried organic phases were evaporated and the residue purified by column chromatography (silica gel, eluent: ethyl acetate/hexanes) to yield 630 mg (31%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:29])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([OH:26])[CH:24]=[CH2:25])=[C:17]([CH3:27])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:28]=1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:29])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([O:26][C:37](=[O:39])[CH3:38])[CH:24]=[CH2:25])=[C:17]([CH3:27])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:28]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reaction time: 0.02 h
Yield: 87 %

Procedure:
To a 100 mL round bottom flask equipped with a magnetic stir bar was added 2-(2,6-dichloro-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.175 g, 0.409 mmol), THF (5 mL), triethylamine (60 μL, 0.43 mmol) and acetic anhydride (1 mL). To the stirring suspension was then added N,N-dimethylaminopyridine (2 mg, 0.016 mmol). The reaction mixture became clear in 1 minute, and TLC analysis indicated that all starting material had been consumed. The reaction mixture was concentrated in vacuo and the residue was further purified by silica gel chromatography, eluting with methanol:dichloromethane (0-10%) to provide acetic acid 1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.168 g, 87%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.42 (s, 1H), 7.80-7.76 (m, 4H), 7.57 (t, 1H, J=8.2 Hz), 6.34 (d, 1H, J=6.3 Hz), 6.21-6.13 (m, 1H), 5.41 (d, 1H, J=17.2 Hz), 5.33 (d, 1H, J=10.2 Hz), 4.25 (s, 3H), 2.33 (s, 3H), 2.12 (s, 3H); ESMS (m/z): found, 471.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=[CH:28][C:29](O)=O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1>>[O:17]1[C:22]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[C:29]3[NH:1][C:2]4[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=4[N:8]=3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C=Cc1ccc2c(c1)OCCO2
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCCO4)nc2n(CCC)c1=O
Yield: 65.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 1.35 g (5.96 mmol) of 5,6-diamino-1,3-dipropyluracil and 1.35 g (6.55 mmol) of 3-(1,4-benzodioxan-6-yl)acrylic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.54 g (yield 65%) of Compound 16 as white needles.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Cc1cc(N2CCCCC2)nc(Cl)n1
Yield: 53.4 %

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (998 mg, 6.0 mmol) in tetrahydrofurane (30 mL) was added under stirring N,N-diisopropyl ethyl amine (853 mg, 6.6 mmol) and piperidine (613 mg, 6.6 mmol) and the reaction was stirred over night at 20° C. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (9:1 to 7:3 v/v) as eluent to yield the title compound (678 mg, 53%) as light yellow crystals. MS ISP (m/e): 212.1/214.3 (100/40) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.70 (s, 1H), 3.58 (m, 4H), 2.22 (s, 3H), 1.61 (m, 2H), 1.51 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]3N=N[N:16]=[C:9]3[C:8]=2[N:17]=1)[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl.[Pt](=O)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH2:16])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2c(cc(C)n3nnnc23)n1CC(C)C
Agent: O=[Pt]=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc(C)cc2n1CC(C)C
Yield: 67.8 %

Procedure:
8-(Ethoxymethyl)-7-(2-methylpropyl)-5-methyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine (6.5 g, 22.5 mmol), trifluoroacetic acid (67 mL), and platinum (IV) oxide (0.47 g) are added to a stainless steel Parr vessel, which is then placed under hydrogen pressure (50 psi, 3.4×105 Pa). For the first eight hours, the vessel is flushed with hydrogen every two hours and then maintained under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. The reaction mixture is filtered through a layer of CELITE filter aid, and the filter cake is washed with additional trifluoroacetic acid. The filtrate is concentrated under reduced pressure to yield a light brown oil, which is dissolved in 37% aqueous hydrochloric acid (25 mL). Sodium carbonate is added to this solution until it exhibits pH 12. The resulting solution is extracted with chloroform. The chloroform solution is dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide about 4 g of 2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine as a white solid.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][CH:17]([CH3:23])[C:18]#[C:19][C:20](O)=[O:21].[CH2:24]([NH2:36])[CH2:25][C:26]1[CH:35]=[CH:34][C:31]([O:32][CH3:33])=[C:28]([O:29][CH3:30])[CH:27]=1>O1CCCC1>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][NH:36][C:20](=[O:21])[C:19]#[C:18][CH:17]([CH3:23])[CH3:16])[CH:35]=[CH:34][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(C)C#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(CCNC(=O)C#CC(C)C)cc1OC
Temperature: 22.5 °C
Reaction time: 48 h
Yield: 62.9 %

Procedure:
38.2 g (280 mmol) of isobutyl chloroformate were added dropwise at 0 to 5° C., as well as 28.3 g (280 mmol) of N-methylmorpholine at 5 to 15° C., to a solution of 28.4 g (254 mmol) of 4-methyl-2-pentynoic acid (ex. 3) in 100 ml of tetrahydrofuran (THF). 46 g (254 mmol) of homoveratrylamine were subsequently added dropwise while cooling with ice and the mixture was allowed to stir at 20 to 25° C. for 48 hours. The reaction solution was then concentrated and the residue was poured into water/10% hydrochloric acid solution and extracted with MTBE. After drying, distilling off the volatile components and chromatographing on silica gel (cyclohexane:MTBE [3:1]), 44 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:10]([O-])=O)[N:3]=1>C(OCC)(=O)C.[Ni]>[NH2:10][C:4]1[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: CNc1ccc(C)nc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CNc1ccc(C)nc1N

Procedure:
8.35 g (50 mMol) of 2-Methyl-5-methylamino-6-nitro-pyridine (Heterocycles 38, 529 (1994)) were dissolved in 300 l ethyl acetate and hydrogenated with 1.5 g Raney nickel for 3.5 hours at room temperature. Then the catalyst was filtered off and the filtrate was evaporated down. After crystallisation of the resulting residue from petroleum ether, 5.75 g (84% of theory) were obtained as olive-green crystals.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)Oc1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (171 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (278 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[C:6](Br)=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)O1.[F-].[Cs+]>COCCOC.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:6]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1sc(-c2ccccc2)c(Br)c1N
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1sc(-c2ccccc2)c(-c2ccc3[nH]ccc3c2)c1N
Yield: 70.3 %

Procedure:
A mixture of EXAMPLE 8A (0.125 g, 0.4 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.122 g, 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (22.4 mg, 0.02 mmol) and cesium fluoride (0.182 g, 1.2 mmol) in 1,2-dimethoxyethane (2 mL) and methanol (1 mL) was heated at 150° C. for 10 minutes under microwave conditions (CEM Discovery). After cooling, the mixture was purified by flash chromatography on silica gel using 3:7 ethyl acetate/hexanes to give 98 mg (71%) of the title compound. 1H NMR (DMSO-d6) δ 11.18 (s, 1H), 7.37-7.43 (m, 3H), 7.17-7.23 (m, 5H), 6.85 (dd, J=8.3, 1.5, 1H), 6.42-6.43 (m, 1H), 5.92 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[Br:19][C:20]1[S:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Br:19][C:20]1[S:24][C:23]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Reactant: OB(O)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(Br)s2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.31) (1.00 g, 2.75 mmol) and commercially available 5-bromthiophene-2-boronic acid (0.570 g, 2.75 mmol) according to the general procedure IVb. Obtained as a light yellow solid (0.480 g, 43%). MS (ISP) 398.0 [(M+H)+] and 400.0 [(M+2+H)+].