Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:18]([CH2:25][C@:26]2([CH3:29])[CH2:28][O:27]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.CN(C=O)C>O>[Cl:16][C:17]1[N:18]([CH2:25][C@@:26]([CH3:29])([OH:27])[CH2:28][N:11]2[CH2:10][CH:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CC=C(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
4-Phenyl-1,2,3,6-tetrahydropyridine hydrochloride (0.495 g, 2.53 mmol) was added to a sodium hydroxide solution, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.5 g, 2.29 mmol) and DMF (5 ml) were added followed by stirring at 70° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)propan-2-ol (0.492 g, yield 57%) as a yellow oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]4[CH:27]=[N:26][CH:25]=[N:24][C:20]=4[NH:21]3)=[CH:17][CH:16]=2)[CH:9]=1)=[O:6].[NH:35]1[CH:39]=[C:38]([CH:40]=[O:41])[N:37]=[CH:36]1.[C:42](=[O:45])([O-])[O-:43].[K+].[K+]>CN(C=O)C.C1COCC1>[F:32][C:31]([F:34])([F:33])[C:42]([OH:43])=[O:45].[CH:40]([C:38]1[N:37]=[CH:36][N:35]([C:2]2[CH:3]=[C:4]([CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([C:15]3[CH:23]=[C:22]4[C:18]([C:19]5[CH:27]=[N:26][CH:25]=[N:24][C:20]=5[NH:21]4)=[CH:17][CH:16]=3)[CH:9]=2)=[O:6])[CH:39]=1)=[O:41]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Reactant: O=Cc1c[nH]cn1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(-n3cnc(C=O)c3)cc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Product: O=C(O)C(F)(F)F
Temperature: 120 °C
Yield: 66.8 %

Procedure:
3-Fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide (0.030 g, 0.064 mmol) was mixed with 1H-imidazole-4-carbaldehyde (0.031 g, 0.32 mmol) and potassium carbonate (0.045 g, 0.32 mol) in DMF (0.7 mL) and was heated at 120° C. for 16 hours. The reaction was then diluted with THF and was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep. LC to give the product (14 mg, 33% yield). 1H NMR (DMSO-d6): δ 13.13 (brs, 1H), 10.57 (s, 1H), 9.84 (s, 1H), 9.67 (s, 1H), 9.16 (s, 1H), 8.88 (d, 1H), 8.71 (d, 1H), 8.62 (m, 1H), 8.44 (m, 1H), 8.40 (d, 1H), 8.29 (m, 1H), 7.75 (m, 2H), 7.58 (s, 1H), 7.47 (m, 1H), 7.39 (m, 1H), 2.27 (s, 3H). MS (EI) m/z=541 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]CCC(N)=O)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=2)[CH:4]=[N:3]1.CC(C)([O-])C.[Na+].[C:29]([C:31]1([NH:34][C:35]([C@H:37]2[N:41]([C:42]([C:44]3([C:47]([F:50])([F:49])[F:48])[CH2:46][CH2:45]3)=[O:43])[CH2:40][C@@H:39](OS(C3C=CC=CC=3)(=O)=O)[CH2:38]2)=[O:36])[CH2:33][CH2:32]1)#[N:30]>O1CCCC1.CN(C)C(=O)C.O>[C:29]([C:31]1([NH:34][C:35]([C@@H:37]2[CH2:38][C@@H:39]([S:13][C:10]3[CH:11]=[CH:12][C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:8][C:9]=3[C:19]([F:21])([F:20])[F:22])[CH2:40][N:41]2[C:42]([C:44]2([C:47]([F:49])([F:50])[F:48])[CH2:46][CH2:45]2)=[O:43])=[O:36])[CH2:33][CH2:32]1)#[N:30]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Reactant: Cn1cc(-c2ccc(SCCC(N)=O)c(C(F)(F)F)c2)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2ccc(S[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)N(C(=O)C4(C(F)(F)F)CC4)C3)c(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.8 %

Procedure:
3-[4-(1-Methyl-1H-pyrazol-4-yl)-2-trifluoromethyl-phenylsulfanyl]-propionamide (16.3 g, 49.6 mmol) was dissolved in tetrahydrofuran (80 mL) before sodium tert-butoxide (4.7 g, 48.9 mmol) was added and the fine suspension was stirred for 2 h at room temperature. N,N-dimethylacetamide (40 mL) was added and the mixture was stirred for further 2.5 h at room temperature. A solution of benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (20 g, 42.4 mmol) in N,N-dimethylacetamide (40 mL) was added and the yellow, fine suspension was stirred for 42 h at room temperature. The mixture was diluted with water (240 mL) and extracted with tert-butyl methyl ether (1×160 mL, 3×80 mL). The combined organic extracts were washed with an aqueous sodium carbonate solution (1 M, 80 mL) and brine (80 mL), dried over sodium sulfate and concentrated in vacuo to yield the title compound as a light brown foam (27.1 g). The crude product (containing dimethylacetamide) was used in the next step without further purification. For characterization purposes, a 2 g sample of crude material was purified by column chromagraphy on silica gel (eluent: gradient ethyl acetate/heptane 4:1 (v/v) to ethyl acetate). Likewise, 1.7 g of purified material were obtained. MS (ESI & APCI): m/z=572.1 [M+H]+, 589.2 [M+NH4]+. 1H NMR (CDCl3, 600 MHz): δ 1.12-1.22 (m, 3H), 1.28-1.34 (m, 3H), 1.49-1.54 (m, 2H), 2.02 (ddd, J=5.6 Hz, 8.2 Hz, 13.6 Hz, 1H), 2.88 (ddd, J=5.7 Hz, 5.7 Hz, 13.7 Hz, 1H), 3.89-3.99 (m, 2H), 3.97 (s, 3H), 4.04-4.09 (m, 1H), 4.69 (dd, J=5.2 Hz, 8.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.60 (bs, 1H), 7.62 (dd, J=1.8 Hz, 8.2 Hz, 1H), 7.69 (s, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.79 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:15]O.[OH-].[Na+]>CO>[Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[CH:11]2[O:15][CH:10]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)C2OC12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4(RS)-t-butyldimethylsilyloxy-2-cyclopentenone (2.12 g; 10 mmoles) was dissolved in 25 ml of methanol. The solution was cooled to 0° C., and 30% aqueous hydrogen peroxide (5 ml; 45 mmoles) was added. Several drops of a 2N aqueous solution of sodium hydroxide were added, and the mixture was stirred for 30 minutes. The methanol was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ether. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give 4(RS)-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone as a crude product. The crude product was dissolved in 20 ml of methanol, and a solution of 1.62 g (10 mmoles) of methyl 6-mercaptohexanoate in 10 ml of methanol was added. Furthermore 1 ml of triethylamine was added. The mixture was stirred at room temperature for 18 hours in an atmosphere of nitrogen. After the reaction, the reaction mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane/ethyl acetate (6/1) as an eluent to give 2.24 g (6.02 mmoles; 60.2%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-methoxycarbonylpentylthio)-2-cyclopentenone.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][O:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[C:34]([O:39][CH3:40])[N:33]=1>>[CH3:30][O:31][C:32]1[N:37]=[C:36]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:35]=[C:34]([O:39][CH3:40])[N:33]=1
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(OC)nc(OC)n2)C3)cc1

Procedure:
Compound ea was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2,6-dimethoxy-4-chloropyrimidine. LC-MS: m/z=+535 (M+H)+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][C:21]1[C:29]2[CH2:28][C:27]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:26][CH2:25][C:24]=2[NH:23][N:22]=1.ClCCl>C(OCC)(=O)C>[CH2:13]([O:12][CH2:11][N:23]1[C:24]2[CH2:25][CH2:26][C:27]3([O:30][CH2:31][CH2:32][O:33]3)[CH2:28][C:29]=2[C:21]([CH3:20])=[N:22]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1n[nH]c2c1CC1(CC2)OCCO1
Reactant: ClCOCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(COCc2ccccc2)c2c1CC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
N-ethyl-N-isopropylpropan-2-amine (4.08 mL) and benzyl chloromethyl ether (0.792 mL) were added to a mixture of 3′-methyl-1′,4′,6′,7′-tetrahydrospiro[1,3-dioxolane-2,5′-indazole] (925 mg) and dichloromethane (20 mL) under ice cooling under an argon gas atmosphere, followed by stirring for 4.5 hours at room temperature. The reaction liquid was diluted with ethyl acetate and then washed with water, saturated aqueous sodium bicarbonate, and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining a mixture (1.11 g) of l′-[(benzyloxy)methyl]-3′-methyl-1′,4′,6′,7′-tetrahydrospiro[1,3-dioxolane-2,5′-indazole] and a regioisomer thereof.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.Cl.[NH:18]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[N:24][CH:25]=1)[NH2:19]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:18]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[N:24][CH:25]=3)[N:19]=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)nc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cn1
Yield: 87 %

Procedure:
A mixture of 1-(4-bromophenyl)-4,4,4-trifluoro-1,3-butanedione (prepared according to the method of J.Med.Chem., 1997, 40, 1347. 1.09 g, 3.71 mmol) and 5-hydrazino-2-pyridinesulfonamide hydrochloride (1.00 g, 4.45 mmol) in ethanol (50 ml) was refluxed for 18 hr. After evaporation, the obtained residue was chromatographed on a column of silica gel (200 g) eluting with ethyl acetate/hexane (1:2) to afford 1.44 g (87%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)([Cl:18])=O.[CH2:20](O)[CH3:21].Cl>O1CCOCC1>[ClH:18].[NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([O:6][CH2:20][CH3:21])=[O:5]
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](CC(=O)O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)c1cccc([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
(S)-3-Amino-3-(3-nitrophenyl)propanoic acid (500 mg, 2.4 mmol) was dissolved in 2.0HCl in dioxane (2 mL) and concentrated in vacuo. In a separate flask thionyl chloride (0.21 mL, 2.8 mmol) was added to ethanol at −10° C. The ethanolic solution was stirred for 20 min at −10° C. then added to the HCl salt of (S)-3-amino-3-(3-nitrophenyl)propanoic acid. The resulting solution was stirred at ambient temperature for 1 h and at 40° C. for 3 h. The reaction mixture was concentrated in vacuo to yield 34A (600 mg, 92%) as a white solid. MS (ESI) m/z 239.09 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15]Br>C(Cl)Cl>[Br:15][C:13]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=2[S:11][C:12]=1[CH3:14]
Reactant: Cc1cc2cccc(C(C)(C)C)c2s1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1sc2c(C(C)(C)C)cccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A solution of 7-tert-butyl-2-methyl-benzo[b]thiophene 94.69 g, 23.0 mmol) in CH2Cl2 (100 mL) is cooled to 0° C. It is treated with Br2 (1.18 mL, 23.0 mmol). The resulting reaction mixture is stirred at rt overnight. It is washed with 10% Na2SO3 (2×50 mL); brine (50 mL); dried with Na2SO4, filtered and concentrated gives the title compound (4.99 g, 17.57 mmol, 76%). 1H NMR (CDCl3): δ 1.53 (s, 9H), 2.56 (s, 3H), 7.32 (dd, J=7.5, 1.3 Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.63 (dd, J=7.5 Hz, 1.3 Hz, 1H) ppm. ES-MS (m/z): calcd for C13H15BrS (M+1)+: 284.2. found: 284.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[N:17]=[C:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)=[CH:28][CH:27]=4)[C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=3)[CH2:11]2)=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:49]([Cl:53])(=[O:52])[CH2:50][CH3:51]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[N:17]=[C:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH:32]5[CH2:37][CH2:36][N:35]([C:49](=[O:52])[CH2:50][CH3:51])[CH2:34][CH2:33]5)=[CH:28][CH:27]=4)[C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=3)[CH2:11]2)=[O:8])=[CH:38][CH:39]=1.[ClH:53]
Reactant: COc1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C(N)=O)c(Nc4ccc(C5CCNCC5)cc4)n3)C2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)c5ccc(OC)cc5)C4)cnc3C(N)=O)cc2)CC1
Product: Cl

Procedure:
Compound 163 (50 mg, 0.085 mmol) was dissolved in 3 mL NMP. To it were added DIEA (74 μL, 0.425 mmol) and then propionyl chloride (23 mg, 0.255 mmol). The reaction was quenched in 10 m using TFA (0.2 mL). The mixture was directly subjected to reverse phase preparative HPLC to isolate (R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-propionylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (170) as HCl salt. MS found for C32H39N7O4 as (M+H)+ 586.2, (M−H)− 584.4. UV: λ=257, 279, 304, 335, 372 nm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:4][C:5]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])=[N:6][C:7]=1[NH:8][C:9]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[NH:11][N:10]=1.[C:32](O)(=O)C.C(N)=N>CCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([N:8]3[CH:32]=[N:1][C:2]4[C:7]3=[N:6][C:5]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH3:19])=[N:4][C:3]=4[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:13]=2)[CH2:16][CH2:15]1
Reactant: CC(=O)O
Reactant: CCOC(=O)c1nc(N[C@@H](C)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1N
Agent: N=CN
Solvent: CCO
Product: CCOC(=O)c1nc(N[C@@H](C)c2ccc(F)cc2)nc2c1ncn2-c1cc(C2CC2)[nH]n1
Yield: 9.5 %

Procedure:
A mixture of (S)-ethyl 5-amino-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]pyrimidine-4-carboxylate (Method 47; 0.6 g, 1.4 mmol) and formamidine acetate (0.32 g, 3.1 mmol) in EtOH (20 ml) was heated to reflux for 12 hours. The reaction was then concentrated, and the resulting residue was dissolved in EtOAc (50 ml) and washed with saturated NaHCO3 solution (50 ml). The organic layer was dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=20:1) to give the title compound (0.058 g, 8%). NMR (400 MHz, CD3OD) 8.48 (s, 1H), 7.45-7.41 (m, 2H), 7.03-6.99 (m, 2H), 6.25 (s, 1H), 5.12-5.03 (m, 1H), 4.50 (q, J=7.2 Hz, 2H), 2.00-1.96 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 1.44 (t, J=7.2 Hz, 3H), 1.10-1.08 (m, 2H), 0.81-0.74 (m, 2H). MS: Calcd.: 435; Found: [M+H]+ 436.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[N+](=[CH2:20])=[N-].C(O)(=O)C>CCOCC>[CH3:20][N:7]1[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=[C:3]1[S:2][CH3:1]
Reactant: CCOC(=O)c1nc(SC)[nH]c1C(=O)OCC
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(SC)n(C)c1C(=O)OCC
Reaction time: 8 h
Yield: 97 %

Procedure:
Diethyl 2-(methylthio)imidazole-4,5-dicarboxylate (10 g; 0.039 tool) was slowly added in small portions to a solution of diazomethane in ether (containing approximately 3 g of diazomethane). Nitrogen was evolved immediately and the solution was allowed to stand at room temperature overnight. Excess diazomethane was then decomposed by the addition of dilute acetic acid and the reaction mixture was worked up in the usual way. Diethyl 1-methyl-2-(methylthio)imidazole-4,5-dicarboxylate (10.2 g; 97%) was obtained as a thick yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=2)=[O:18])=[N:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O[C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1N=CC=C2.IC1C=CC=CC=1>CS(C)=O.[Cu]I>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][N:22]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:43]=3)[C:21](=[O:25])[CH:20]=2)=[O:18])=[N:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2cccnc12
Reactant: Cc1nc(NC(=O)c2cc[nH]c(=O)c2)sc1C(=O)NCc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Ic1ccccc1
Product: Cc1nc(NC(=O)c2ccn(-c3ccccc3)c(=O)c2)sc1C(=O)NCc1ccccc1
Temperature: 130 °C
Yield: 20 %

Procedure:
To a degassed solution of N-benzyl-4-methyl-2-(2-oxo-1,2-dihydropyridine-4-carboxamido)thiazole-5-carboxamide (0.060 g, 0.16 mmol), potassium carbonate (0.033 g, 0.24 mmol) and 8-hydroxyquinoline (0.0034 g, 0.024 mmol) in dimethyl sulfoxide (5 mL) were added iodobenzene (0.039 g, 0.19 mmol) and finally copper(I) iodide (0.0046 g, 0.025 mmol). The reaction mixture was heated at 130° C. for 16 hours, then cooled to ambient temperature and filtered. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (40 mL) and washed with saturated aqueous sodium bicarbonate solution (2×20 mL), and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrate in vacuo. The residue was recrystallized from ethyl acetate and methanol to yield a colorless solid in 20% yield (0.012 g); m.p. 260-262° C.; 1H NMR (DMSO-d6, 300 MHz) δ 13.11 (s, br., 1H), 8.63 (t, J=5.8 Hz, 1H), 7.78 (d, J=7.1 Hz, 1H), 7.58-7.37 (m, 5H), 7.35-7.26 (m, 4H), 7.23-7.18 (m, 1H), 7.14 (d, J=1.5 Hz, 1H), 6.75 (dd, J=1.5, 7.1 Hz, 1H), 4.38 (d, J=5.8 Hz, 2H), 2.51 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 165.5, 162.0, 162.0, 161.3, 140.7, 140.2, 140.0, 139.9, 137.9, 129.6, 128.9, 128.7, 127.7, 127.2, 127.0, 120.9, 103.7, 43.1, 16.9; MS (ES+) m/z 445.0 (M+1).
Reaction SMILES: C(O[CH:5]([CH3:24])/[CH:6]=[CH:7]/[C:8]1[S:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[N:10][CH:9]=1)(=O)C.[N-:25]=[N+:26]=[N-:27].[Na+].CCOCC.CCCCCC>O1CCCC1.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>[N:25]([CH:5]([CH3:24])/[CH:6]=[CH:7]/[C:8]1[S:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[N:10][CH:9]=1)=[N+:26]=[N-:27]
Reactant: CC(=O)OC(C)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Reactant: [N-]=[N+]=[N-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1)N=[N+]=[N-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of the product of Example 7E (155 mg, 0.45 mmole) in tetrahydrofuran (15 mL) was added sodium azide (32 mg, 0.5 mmole) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmole) and heated at 50° C. After 2 hours additional sodium azide (23 mg, 0.35 mmole) was added and after 8 hours a third amount of sodium azide (40 mg, 0.61 mmole) was added and stirred at 50° C. overnight. The reaction mixture was added ether and hexane and the organic phase was washed twice with water followed by brine. The reaction mixture was dried over magnesium sulfate filtered and evaporated. The product was purified via silica column, using a gradient of 5-25% ethyl acetate in hexane and yielded 85 mg (57.6%) of clear oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.13-7.22 (m, 2H) 7.10 (s, 1H) 6.86-6.98 (m, 2H) 6.58 (d, J=15.44 Hz, 1H) 5.69 (dd, J=15.63, 7.17 Hz, 1H) 4.42-4.62 (m, 1H) 3.96-4.23 (m, 1H) 1.35 (d, J=5.88 Hz, 6H) 1.33 (d, J=5.88 Hz, 3H). Mass spectrum DCI 331 (M+H)+.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]=[O:20])(=O)=O)C=CC=CC=1.[OH-].[K+]>CO.O>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[C:11]1[CH:19]=[O:20]
Reactant: O=Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2.5 g, 8.73 mmol) in methanol (50 mL) stirred under nitrogen at r.t. was added a solution of KOH (1.96 g, 34.9 mmol) in water (5 mL) dropwise during 1 min. The reaction mixture was stirred at r.t. for 30 min, TLC showed complete conversion. The reaction mixture was diluted with H2O (150 mL), extracted with dichloromethane (3×150 mL) and the organic phase was washed with saturated brine (3×50 mL), water 100 mL, dried over sodium sulfate and evaporated in vacuo to give the title compound as a yellow solid (1 g, 54.9% yield) which was used in the next reaction without further purification.
Reaction SMILES: C(#N)C.[OH:4][CH:5]1[CH:9]2[O:10][C:11](=[O:21])[CH:12]3[CH:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]1[CH2:7][CH:8]23.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>O>[C:29]([O:4][CH:5]1[CH:9]2[O:10][C:11](=[O:21])[CH:12]3[CH:13]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH:6]1[CH2:7][CH:8]23)(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: C=C(C)C(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
Dissolved into 900 mL of acetonitrile were 226.8 g of tert-butyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta[b]furane-7-carboxylate (24) and 135.2 g of triethylamine. Into this mixture was gradually added 121.1 g of methacryloyl chloride at 20° C. or lower. After the resulting mixture was stirred at room temperature for 3 hours, 300 g of water was added into it and usual work-up was carried out. Recrystallization was made from ethyl acetate to give 202.2 g of the intended product (Yield 70%).