Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35](Cl)=[CH:34][C:33]=4Cl)[C@@H:16]([O:17]CC4C=CC(Cl)=CC=4Cl)[C@@:13]3([CH3:40])[O:14][CH3:15])[C:6]=2[N:7]=1>CO.CCN(CC)CC.[Pd]>[NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@@H:16]([OH:17])[C@@:13]3([CH3:40])[O:14][CH3:15])[C:6]=2[N:7]=1
Reactant: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(C)c2c(=O)[nH]c(N)nc21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CO[C@]1(C)[C@H](O)[C@@H](COCc2ccccc2)O[C@H]1n1cc(C)c2c(=O)[nH]c(N)nc21
Reaction time: 36 h

Procedure:
A mixture of the product from Step C (64 mg, 0.1 mmol) in MeOH (5 mL) and Et3N (0.2 mL) and 10% Pd/C (24 mg) was hydrogenated on a Parr hydrogenator at 50 psi at r.t. for 1.5 days, then filtered through a Celite pad which was thoroughly washed with MeOH. The combined filtrate was evaporated and the residue purified on a silica gel column (3×4 cm) with CH2Cl2/MeOH (30/1, 20/1) as eluent to yield 2-amino-5-methyl-7-(5-O-benzyl-2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one. The compound (37 mg) was further hydrogenated in EtOH (2 mL) with 10% Pd/C and under atmospheric pressure of hydrogen. After stirring 2 days at r.t., the reaction mixture was filtered through Celite, the filtrate evaporated and the crude product purified on a silica gel column (1×7 cm) with CH2Cl2/MeOH (30/1, 20/1 and 10/1) as eluent to yield the title compound (12 mg) after freeze-drying.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[F:13][CH:14]([F:29])[C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=2)[CH:18]=[CH:19][CH:20]=1.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:23]3[C:24](=[O:28])[CH2:25][CH2:26][CH2:27][C:22]=3[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]([F:13])[F:29])[CH:16]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(Nc2cccc(C(F)F)c2)CCC1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Solvent: O
Solvent: ClCCl
Product: O=C1CCCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (400 mg, 1.62 mmol) in dichloromethane (2.5 mL) is added to a solution of 3-(3-(difluoromethyl)phenylamino)-cyclohex-2-enone (intermediate 32, 385 mg, 1.62 mmol) in dichloromethane (2.5 mL). The mixture is heated at reflux for 2 h and cooled to room temperature. Water is added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 80:20 to ethyl acetate. Yield: 350 mg; ESI mass spectrum: [(79Br)-M+H]+=447, [(81Br)-M+H]+=449; Retention time HPLC: 0.61 min (X012_S01).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:5]=3[C:4]=2[C:3]=1[Cl:29].[OH-].[K+].Cl>C1COCC1.O>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][C:5]2[C:4]3[C:3]([Cl:29])=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=3[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Temperature: 60 °C

Procedure:
To a solution of tert-butyl 9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 3.4 mmol) in THF (15 mL), a solution of KOH (25 mg, 4.4 mmol) dissolved in H2O (10 mL) was added and heated to 60° C. The reaction was cooled to rt after 2 h. The reaction was made acidic with 10% aqueous HCl and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and the crude acid was concentrated: 1H NMR (300 MHz, DMSO) δ 13.11 (br s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 5.04 (s, 2H), 3.62 (m, 4H), 2.93 (m, 2H), 1.41 (s, 9H); HRMS (FAB) calcd for C19H22Cl2N2O4+H 413.1035, found 413.1050.
Reaction SMILES: O[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)c1ccccc1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Br)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a cooled (0° C.) solution of 0.425 g (2.19 mmol) of the product of Step B dissolved in 10 mL of dichloromethane was added 0.717 g (2.74 mmol) of triphenylphosphine followed by 0.908 g (2.74 mmol) of carbon tetrabromide. After 30 minutes the reaction was allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.373 g (66%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:28]=[C:29]6[NH:35][C:34]([NH:36]C(=O)OC)=[N:33][C:30]6=[N:31][CH:32]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.Cl>CO.[OH-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:28]=[C:29]6[NH:35][C:34]([NH2:36])=[N:33][C:30]6=[N:31][CH:32]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc(C)c3Cc3ccc(F)cc3)CCO4)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncnc(N2CCOc3ccc(-c4cnc5nc(N)[nH]c5c4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
A mixture of methyl [6-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate (15 mg, 0.028 mmol) in methanol and 2 M aqueous potassium hydroxide (1:1, 2 mL) was stirred at 65° C. for 18 hours. The reaction mixture was cooled, adjusted to pH 10 with 2 N hydrochloric acid, concentrated, diluted with ethyl acetate (10 mL), washed with brine solution (5 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative reverse phase HPLC to give 6-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-amine (8.9 mg, 67% yield). 1H NMR (400 MHz, DMSO-D6): 8.46 (1H), 8.02 (br, 1H), 7.47 (d, 1H), 7.39 (dd, 1H), 7.10 to 6.96 (m, 5H), 7.75 (br, 1H), 4.53 (s, 2H), 4.30 (m, 2H), 4.00 (s, 2H), 3.89 (m, 2H), 2.22 (s, 3H), MS (EI) for C27H24FN7O: 428 (MH+).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[CH:28]=[N:27][N:26]=1.[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[CH:28]=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:53]([NH:52][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:54])=[O:43]
Reactant: O=C=Nc1ccccc1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CNC(=O)Nc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazole di-p-toluenesulfonate (5.0 g) was dissolved in dimethylformamide (20 ml). Phenyl isocyanate (0.87 ml) and triethylamine (3.0 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 2.47 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-3-ylmethyl)-N'-phenylurea.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1>[C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][C:44](=[O:46])[CH3:45])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
A mixture of 0.312 g of 3 -hydroxy-7β-phenylacetylamino-cepham-4α-carboxylic acid diphenylmethyl ester in 15 ml of pyridine and 7 ml of acetic anhydride is left to stand for 16 hours at 0° C and after addition of 50 ml of toluene is evaporated under reduced pressure. The residue is taken up in ethyl acetate; the organic solution is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by means of preparative thin layer chromatography; a silica gel plate of 100 cm length is used and development is carried out with a 1:1 mixture of toluene and ethyl acetate. 3 -Acetoxy-7β-phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester of Rf = 0.47 is obtained, melting at 162°-164° C after crystallisation from a mixture of methylene chloride and pentane; [α]D20 = + 55° ± 1° (c = 0.492 in chloroform); ultraviolet absorption spectrum (in 95% strength ethanol): λmax = 253 mμ (ε = 700), 258 mμ (ε = 820) and 265 mμ (ε = 660): infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96μ, 5.66μ, 5.77μ, 5.97μ, 6.28μ and 6.71μ.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9].N>C1COCC1>[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]([NH2:9])=[O:2]
Reactant: CC(C)C(C)(N)C#N
Reactant: O=S(=O)(O)O
Agent: N
Solvent: C1CCOC1
Product: CC(C)C(C)(N)C(N)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid (29.7 ml) is cooled with stirring in an ice-acetone cooling bath. To the acid is added 11.8 g (-)-2-amino-2,3-dimethylbutyronitrile with [α]D25 =-7.31° (C=0.0368 g/ml THF) at such a rate that the temperature does not go above 25° C. After the addition, the temperature of the reaction mixture is slowly raised to 100° C. and held at that temperature for one hour. After cooling the mixture in an ice-acetone bath, 85 ml concentrated ammonia is added at such a rate that the temperature does not exceed 75° C. The mixture is extracted five times with methylene chloride, the combined extracts dried and concentrated. This gives 11.95 g of white solid, mp 79°-81° C. and [α]D25 =+57.43° (c=0.0213 g/ml THF). This solid is recrystallized from methylene chloride-hexane to give 11.2 g of (+)-2-amino-2,3-dimethylbutyramide, mp 81°-82° C. [α]D25 =+59.38° (c=0.0162 g/ml THF).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=O)=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=[N:22][OH:23])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=O)n2C)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=NO)n2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
In 2 ml of ethanol was dissolved 50 g (0.17 mmol)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole-2-carbaldehyde (Compound I-6), followed by addition of 36 mg (0.5 mmol)of hydroxylamine hydrochloride and 43 mg (0.5 mmol) of sodium acetate, and the mixture was stirred for 30 minutes at room temperature. To this reaction mixture, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was washed with ethyl acetate to precipitate the product, and 32 mg (yield 60%)of Compound I-10 was obtained by the filtration. mp 240-241° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(O)(=O)C.Br.[OH-].[Na+]>O>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(-c2nc(-c3ccccc3)[nH]c2-c2ccc(OC)cc2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc(-c3ccccc3)[nH]c2-c2ccc(O)cc2)cc1
Yield: 79.6 %

Procedure:
4,5-Bis(4-methoxyphenyl)-2-phenylimidazole (15.8 g, 0.044 mol) was placed in a 250 ml three neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, thermometer, reflux condenser and hydrogen bromide gas trap along with acetic acid (75 ml) and 47-49% aqueous hydrogen bromide solution (130 ml). The mixture was heated to reflux for 16 hours, cooled, poured into water to give a white solid, which was neutralized with sodium hydroxide, collected, washed with water and dried at 100° C. Yield was 13.7 g of white solid. Recrystallization from ethanol/water (3:1) gave 11.5 g (79%) of white crystals, m.p. 327°-330° C. Anal. Calcd. for C21H16N2O2 : C, 76.80%; H, 4.91%; N, 8.53%. Found: C, 76.50%; H, 5.00%; N, 8.44%.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[C:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:22](=[O:23])[CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:7][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (45 mg, 0.20 mmol) and diphenyl-acetic acid (42 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (10.3 mg, 0.0246 mmol, 12%). ESI-MS m/z calc. 418.1. found 419.2 (M+1)+ Retention time 3.85 minutes. 1H NMR (400 MHz, DMSO-d6) δ 4.19 (s, 2H), 5.30 (s, 1H), 7.23-7.47 (m, 15H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[N:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:3][CH2:2]1>C(O)C.O1CCCC1.[OH-].[Na+]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[N:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCC4CC4)cc3c2C)C(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)nc2)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Ethyl 3-[{[5-({1-[5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate (280 mg) synthesized in Example A212 was dissolved in ethanol (1.0 mL)-tetrahydrofuran (1.0 mL), 1N aqueous sodium hydroxide solution (1.1 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, water (2.0 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (1.1 mL) under ice-cooling, and stirred for 30 min. The resulting precipitate was collected by filtration, and dried to give the title compound (238 mg, 90%) as a colorless solid.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Ic1cccs1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cccs2)cc1

Procedure:
2-Iodothiophene and 4-methylphenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(4-methylphenyl)thiophene as colorless crystals. APCI-Mass m/Z 175 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20].I[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>O>[CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Reactant: CC(C)(C)OC(=O)NCCCI
Solvent: O
Product: CCCc1nc2cnc3cc(OCCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)C

Procedure:
A modification of the general method described in Part L of Example 2 was used to treat 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol with tert-butyl 3-iodopropylcarbamate. The reaction mixture was diluted with water; a precipitate formed. The precipitate was isolated by filtration, washed with water and then with diethyl ether until the filtrate was clear, and dried overnight in a vacuum oven at 60° C. to yield tert-butyl 3-{[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate as a tan powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[CH3:19])=O)[CH:2]=1.O.NN.[OH-].[K+].O>C(O)CO>[Br:18][C:15]1[CH:16]=[CH:17][C:11]2[C:10]([CH3:19])=[C:9]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[S:13][C:12]=2[CH:14]=1
Reactant: Cc1c(C(=O)c2cccnc2)sc2cc(Br)ccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1c(Cc2cccnc2)sc2cc(Br)ccc12
Yield: 77.7 %

Procedure:
A mixture of 6-bromo-3-methylbenzo[b]thien-2-yl pyrid-3-yl ketone (4.30 g) and hydrazine hydrate (2.60 g) in ethylene glycol (30 ml) was heated under reflux for 2 hours and then cooled. Potassium hydroxide (2.80 g) was added and the temperature was gradually raised to reflux. After heating under reflux for a further 3 hours the solution was cooled and poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform/petrol (b.p. 40°-60°). (3:1) gave 6-bromo-3-methyl-2-(3-pyridylmethyl)benzo[b]thiophene (3.20 g). A sample crystallised from petrol (b.p. 40°-60°) had m.p. 69°-70°.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4([CH2:24][CH:17]4[N:12]3[C:13](=[O:16])[C:14]=2[CH3:15])[C:21]([OH:23])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4([CH2:24][CH:17]4[N:12]3[C:13](=[O:16])[C:14]=2[CH3:15])[C:21]([O:23][CH3:27])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(/C=C/c2ccccc2)nc2n(c1=O)C1CC1(C(=O)O)C=C2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C12C=Cc3nc(/C=C/c4ccccc4)c(C)c(=O)n3C1C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (0.8 g) was reacted with methyl iodide (0.55 g) and anhydrous K2CO3 (0.65 g) in dimethylformamide (7 ml) under stirring at room temperature for 4 hours. After dilution with ice water the precipitate was filtered off: crystallization from acetone gave 0.5 g of 2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester, m.p. 164°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1/[CH:21]=[CH:22]/[C:23]([OH:25])=O.[CH3:26][NH2:27]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1/[CH:21]=[CH:22]/[C:23]([NH:27][CH3:26])=[O:25]
Reactant: COc1cccc(-c2ccc3c(/C=C/C(=O)O)c(OC)ccc3c2)c1
Reactant: CN
Product: CNC(=O)/C=C/c1c(OC)ccc2cc(-c3cccc(OC)c3)ccc12

Procedure:
The compound was prepared by reaction of (E)-3-(2-methoxy-6-(3-methoxyphenyl)naphthalene-1-yl)acrylic acid (200 mg, 0.60 mmol, 1 eq) with 33% methylamine (1 eq) according to method D. Purification by column chromatography was not necessary. The desired compound was obtained in quantitative yield.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([S:13][CH3:14])[N:7]=1>C1COCC1>[CH:1]([NH:4][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([S:13][CH3:14])[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CSc1nc(C)cc(Cl)n1
Solvent: C1CCOC1
Product: CSc1nc(C)cc(NC(C)C)n1
Reaction time: 8 h

Procedure:
Isopropylamine (100 mL) was added very slowly to 22.0 g (125.96 mmol) of crude 4-chloro-6-methyl-2-(methylthio)pyrimidine in 70 mL of THF in a 350 mL pressure tube. NOTE: Residual POCl3 caused smoking and bubbling, therefore the addition was done at 0° C. Once acid was quenched, an additional 50 mL of isopropylamine was added and the pressure tube was sealed. The reaction vessel was brought to 60° C. and stirred overnight. The LCMS indicate very little starting material. Solvent was evaporated leaving N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine as a viscous yellow oil. The crude material was taken directly to the next step.