Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([NH2:21])=[O:20])[CH:16]=[C:15]([C@@H:22]([OH:25])[CH2:23][OH:24])[N:14]=3)=[CH:9][CH:8]=2)=[C:4]([F:28])[CH:3]=1.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([NH2:21])=[O:20])[CH:16]=[C:15]([C@H:22]([OH:25])[CH2:23][OH:24])[N:14]=3)=[CH:11][CH:12]=2)=[C:4]([F:28])[CH:3]=1
Reactant: NC(=O)c1cc([C@@H](O)CO)nc(-c2ccc(Oc3ccc(Cl)cc3F)cc2)n1
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Product: NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(Cl)cc3F)cc2)n1

Procedure:
(S)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide (Compound Example No. 10) was prepared in a similar fashion to (R)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide (Compound Example No. 9) using AD-mix-α instead of AD-Mix-β. 1H NMR (400 MHz, CD3OD): 8.49 (2H, d, J=8.8 Hz), 8.03 (1H, s), 7.30 (1H, dd, J=2.4, 10 Hz), 7.18-7.10 (2H, m), 6.96 (2H, d, J=9.2 Hz), 4.73 (1H, dd, J=3.6, 6.4 Hz), 3.89 (1H, dd, J=3.6, 11 Hz), 3.75 (1H, dd, J=6.0, 11 Hz); LC/MS: m/z=404[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10](=[S:14])[NH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH3:18]I>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10]([S:14][CH3:18])=[N:11][C:12]=2[CH3:13])=[CH:16][CH:17]=1
Reactant: CI
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1Cc1ccc(Cl)cc1
Product: CSc1nc(C)c(Cc2ccc(Cl)cc2)c(=O)[nH]1

Procedure:
5-(4-Chlorobenzyl)-6-methyl-2-thiouracil was methylated with methyl iodide as described in Example 1 (i) to give 5-(4-chlorobenzyl)-6-methyl-2-methylthio-4-pyrimidone (m.p. 248°-251°).
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[CH3:18][C@H:19]([NH2:30])[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(Cl)(Cl)Cl>CO>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([CH2:2][NH:30][CH:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH3:18])[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(C)c1cccc3ccccc13)C2
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.48 g, 5.04 mmol) and S-(-)-1-(1-naphthyl)ethylamine (1.75 g, 10.2 mmol) was stirred in a hot bath at 150° C. for 3 hours. The reaction product was subjected to silica gel column chromatography (developer=chloroform: methanol=50:1) to obtain 1.78 g (91.9%) of a crude target material as a mixture of 2 types of diastereomers which are different at the position C-2. This product was further subjected to silica gel column chromatography (developer=chloroform: methanol=100:1), and the first eluted fraction was condensed under reduced pressure. As a result, 535 mg of a first diastereomer of the title compound was obtained as pale yellow powder (27.6%)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22](O)=[O:23])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.C(OC(=O)[NH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([C:38](=[O:43])[NH:39][CH:40]2[CH2:42][CH2:41]2)[CH2:34][CH2:33]1)(C)(C)C>>[CH:40]1([NH:39][C:38]([C@H:35]2[CH2:36][CH2:37][C@H:32]([NH:31][C:22]([C:19]3[C:15]4[N:16]=[CH:17][N:18]=[C:13]([C:7]5[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=5[O:5][CH2:4][CH:1]5[CH2:3][CH2:2]5)[C:14]=4[NH:21][CH:20]=3)=[O:23])[CH2:33][CH2:34]2)=[O:43])[CH2:42][CH2:41]1
Reactant: O=C(O)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)NC2CC2)CC1
Product: O=C(N[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A77) and trans-(4-cyclopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (A195) the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][C:16]([O:18]C)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>CCOCC>[OH:18][C:16]([C:2]1[CH:21]=[CH:20][CH:5]=[CH:4][CH:3]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=2)[CH2:8][CH2:9]1
Reactant: COC(=O)CCN1CCCN(Cc2ccc(Cl)cc2)CC1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCN1CCCN(Cc2ccc(Cl)cc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 54 mg of methyl 3-[4-(4-chlorobenzyl) homopiperazinyl]propionate in 10 mL of ether was mixed with under nitrogen, 4 mL of 1 M phenyl magnesium bromide. The mixture was stirred at room temperature for 30 minutes, mixed with aqueous saturated ammonium chloride and the mixture was extracted with 50 mL of ethyl acetate. The extract was washed with 50 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate/methanol 9:1) to give 65 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17]O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([NH:27][CH2:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2CNC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To [2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methanol prepared in step A of example 1 (0.150 g, 0.60 mmol) in 5 mL of THF at 0° C. was added thionyl chloride (0.22 mL, 5 eq). The reaction mixture was refluxed for 45 minutes and then the solvent and the excess of thionyl chloride were evaporated. The residue was suspended in 5 mL of acetonitrile and tert-butylamine (0.62 mL, 10 eq) was added at 0° C. The solution was stirred 48 h at room temperature, evaporated and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with ethyl acetate and then the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was thoroughly washed with pentane and filtered off to yield expected compound as an orange powder (0.192 g, quantitative yield) m/z (ESI) 307.2 [M+H]+.
Reaction SMILES: CN1CCOCC1.[NH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[NH:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[NH:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:15]([C:23]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
1.01 g of N-methylmorpholine is added to a solution in 60 ml of methylene dichloride of 6.39 g of H-Phe-Gly-AHCP-Ile-AMPA [obtainable by subjecting H-Gly-OMe to a condensation reaction with BOC-Phe-OH to give BOC-Phe-Gly-OMe, saponifying the latter and subjecting the product to a condensation reaction with H-AHCP-Ile-AMPA to give BOC-Phe-Gly-AHCP-Ile-AMPA and splitting off the BOC group]. 2.43 g of 4-BOC-aminocyclohexanecarbonylic acid, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of methylene dichloride are added with stirring, the mixture is stirred for 14 hours at 0°-10°, the precipitated dicyclohexylurea is filtered off and the manner gives 4-BOC-aminocyclohexylcarbonyl-Phe-Gly-AHCP-Ile-AMPA, m.p. 141°-143°.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3]C1C(O)=O.[Li]C.[CH3:15][C:16]([CH3:18])=[O:17].C1CNC(=O)C1.[Br:25][Br-]Br>CO>[Br:25][CH2:15][C:16]([CH:18]1[CH2:1][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3]1)=[O:17]
Reactant: O=C(O)C1CC2CCCCC2C1
Reactant: CC(C)=O
Agent: O=C1CCCN1
Agent: [Li]C
Solvent: CO
Product: O=C(CBr)C1CC2CCCCC2C1
Yield: 84 %

Procedure:
Octahydro-indene-2-carboxylic acid (490 mg, 2.92 mmol) was treated with MeLi following a method analogous to General Procedure A1 to produce the corresponding methyl ketone. The methyl ketone in MeOH was then treated with pyrrolidone hydrotribromide following a method analogous to General Procedure B1 to produce 2-bromo-1-(octahydro-inden-2-yl)-ethanone (600 mg, 84% overall crude yield). The above obtained bromoketone (150 mg, 0.61 mmol) was treated with 3-[1-(5-methyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (150 mg) following a method analogous to General Procedure C to produce the aminothiazole propionic acid ester: 3-{(5-methyl-thiophen-2-ylmethyl)-[4-(octahydro-inden-2-yl)-thiazol-2-yl]-amino}-propionic acid tert-butyl ester.
Reaction SMILES: [N:1]([CH:4]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH2:1])[C:10]=12
Reactant: [N-]=[N+]=NC1CCCCc2cccnc21
Agent: [Pd]
Solvent: CO
Product: NC1CCCCc2cccnc21
Yield: 88 %

Procedure:
To a solution of the azide (23.18 g, 0.123 mol) in methanol (150 mL) was added Palladium, 10 wt. % on activated carbon (1.95 g) and the resultant mixture was hydrogenated at 40 psi on a Parr shaker. The mixture was vacuum filtered through celite and the cake was washed with methanol. The solvent was removed from the filtrate under reduced pressure and the oil obtained was distilled (Kugelrohr, bp 105-140° C. @ 0.2 Torr) to provide 17.56 g (88%) of 6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine as a pale yellow oil. 1H NMR (CDCl3) δ 1.23-1.37 (m, 1H), 1.43-1.57 (m, 1H), 1.78-2.10 (m, 6H) including 2.04 (s, 2H), 2.71-2.85 (m, 2H), 4.19 (dd, 1H, J=10.0, 1.5), 7.05 (dd, 1H, J=7.4, 4.9 Hz), 7.36 (d, 1H, J=5.9 Hz), 8.38 (d, 1H, J=4.9 Hz).
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[Na].[CH3:17][CH:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]>CN(C)C=O>[CH2:1]([N:4]([CH:18]([CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNS(=O)(=O)c1ccccc1
Reactant: CC(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=CCN(C(C)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.97 g (0.01 mole) of N-allylbenzenesulfonamide was added to 0.58 g (0.012 mole) of 50% sodium hydride in 15 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes to react them. To the resulting sodium salt was added 2.10 g (0.012 mole) of α-methyl-2-chlorobenzyl chloride. The mixture was stirred at room temperature for 1 hour. The N,N-dimethyl formamide was distilled off under reduced pressure, and cold water was added. The resulting oil layer was extracted with benzene. The benzene layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography to afford the final product. The final product is designated as compound No. 89 in Table 2, and its melting point and elemental analysis values are shown in Table 2.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[C:12]([O:17][CH3:18])[C:11]([O:19][CH3:20])=[C:10]([O:21][CH3:22])[CH:9]=3)=[CH:4][CH:3]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CO>[C:27]([CH2:26][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[C:12]([O:17][CH3:18])[C:11]([O:19][CH3:20])=[C:10]([O:21][CH3:22])[CH:9]=3)=[CH:23][CH:24]=1)([O:29][CH2:30][CH3:31])=[O:28]
Reactant: COc1cc2oc(-c3ccc(N)cc3)cc(=O)c2c(OC)c1OC
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)CNc1ccc(-c2cc(=O)c3c(OC)c(OC)c(OC)cc3o2)cc1

Procedure:
Similar to the preparation of 12a, the title compound is prepared from the reaction of 4′-amino-5,6,7-trimethoxyflavone, 10a, (654 mg, 2 mmol), ethyl bromoacetate (367 mg, 2.2 mmol), and anhydrous potassium carbonate (0.5 g) in methanol (40 ml).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.N12CCCN=C1CCCC[CH2:12]2>ClCCl.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:12])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C1CCC2=NCCCN2CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: ClCCl
Product: C=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.0 g (49.3 mmol) of 4-bromo-2-fluorobenzaldehyde were dissolved in 40 ml of dichloromethane, admixed with 9.6 ml (9.7 g, 64.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 19.4 g (54.2 mmol) of methyltriphenylphosphonium bromide and stirred at RT for 3 h. The reaction mixture was purified on silica gel (eluent: dichloromethane). The product fractions were combined, concentrated under reduced pressure and dried under high vacuum. Yield: 4.5 g (41% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 49.3 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (104 mg, 49%). MS (ISP) 423.3 [(M+H)+]; mp 227° C.
Reaction SMILES: O[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.CO.COCCOCCO.S(=O)(=O)(O)O>[Zn].O>[NH2:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CO
Solvent: COCCOCCO
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C

Procedure:
50 Parts of 1-hydroxylaminoanthraquinone was stirred into a mixture of 700 parts of diethyleneglycol monomethyl ether, 100 parts of water and 30 parts of conc. sulfuric acid, then added thereto little by little 16 parts of zinc dust over 1 hour after heating to 80°C. The reaction mixture was maintained at 80°C for additional 2 hours and then filtered. The filtrate was washed with water and dried to obtain 43.5 parts of 1-aminoanthraquinone of a purity of 94 %.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][C:8]([NH2:10])=[S:9])=[N:2]1.[O-]CC.[Na+].[C:15]([CH2:17][C:18](OCC)=[O:19])#[N:16]>>[NH2:16][C:15]1[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[C:8](=[S:9])[NH:10][C:18](=[O:19])[CH:17]=1
Reactant: NC(=S)NCc1cc[nH]n1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Product: Nc1cc(=O)[nH]c(=S)n1Cc1cc[nH]n1
Temperature: 5 °C
Yield: 44 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(b) by using 1-(1H-pyrazol-3-ylmethyl)thiourea (1.39 g, 8.87 mmol obtained from Example 13(a)), sodium ethoxide (21% w/v, 8.62 mL, 26.6 mmol) and ethyl cyanoacetate (2.84 mL, 26.6 mmol) with the exception that it was necessary to maintain the cloudy solution at 5° C. overnight to obtain precipitation (0.87 g, 44% yield).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([C:15]3[S:16][C:17]([C:20]4[CH:25]=[C:24]([NH:26][C:27]5[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=5)[CH:23]=[C:22]([CH3:37])[CH:21]=4)=[CH:18][N:19]=3)[C:9]2=[O:38])=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>ClCCl>[CH3:37][C:22]1[CH:21]=[C:20]([C:17]2[S:16][C:15]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][NH:8][C:9]3=[O:38])=[N:19][CH:18]=2)[CH:25]=[C:24]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:23]=1
Reactant: COc1ccc(CN2CCCCC(c3ncc(-c4cc(C)cc(Nc5nccc(C(F)(F)F)n5)c4)s3)C2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCCCNC3=O)s2)c1
Yield: 26.9 %

Procedure:
To a microwave vial, were added the product of Step 2 (44.4 mg, 0.078 mmol), trifluoroacetic acid (0.3 ml, 3.89 mmol), trifluoromethanesulfonic acid (10 μl, 0.078 mmol) and dichloromethane (1 ml). The mixture was irradiated at 110° C. in the microwave for 40 min. The mixture was then purified by reverse phase HPLC to afford the title compound (12 mg, 0.021 mmol, 27.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([NH2:12])=[N:6][NH:7]2.CC(N(CC1C=CC=C(CN2C3C(=C(C(=O)C)C=CC=3)C(NS(C3SC(Cl)=CC=3)(=O)=O)=N2)C=1)C(=O)[O-])(C)C.[OH-].[K+].Br[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([F:63])[CH:56]=1>CS(C)=O.C(OCC)(=O)C.ClCCl>[F:63][C:57]1[CH:56]=[C:55]([CH2:54][N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[C:5]([NH2:12])=[N:6]2)[CH:60]=[CH:59][C:58]=1[O:61][CH3:62]
Reactant: COc1cccc2[nH]nc(N)c12
Reactant: COc1ccc(CBr)cc1F
Agent: CC(=O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN(C(=O)[O-])C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
4-(Methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (490 mg, 3 mmol) and potassium hydroxide (185 mg, 3.30 mmol) were dissolved in DMSO (30 mL). The reaction was left to stir for 30 min, before 4-(bromomethyl)-2-fluoro-1-(methyloxy)benzene (657 mg, 3.00 mmol) was added to the reaction mixture and stirred for 1 h at room temperature under nitrogen. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with water (2×250 mL) and brine (250 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered before being evaporated in vacuo to afford a brown oil. The residue was loaded in dichloromethane on a silica 100 g cartridge and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo and the residue re-purified by chromatography on silica 70 g using a 0-50% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (432 mg, 48%) as an off-white solid. LCMS (System A) RT=0.96 min, ES+ve m/z 302 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C@H:24]1[C@@H:27]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26](=[O:39])[NH:25]1.C(N(CC)CC)C>O1CCCC1>[OH:3][CH:2]([N:25]1[C:26](=[O:39])[C@H:27]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:24]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:14]1[O:13][CH2:17][CH2:16][O:15]1)[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=CC(=O)OCc1ccccc1
Reactant: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1c1ccccc1C1OCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N(C(O)C(=O)OCc2ccccc2)[C@H]1c1ccccc1C1OCCO1
Reaction time: 1.5 h

Procedure:
Freshly distilled benzyl glyoxylate (312 mg, 1.9 mmol) and freshly distilled tetrahydrofuran (15 ml) were stirred with 4A molecular sieves for one hour and then cooled in ice. To this solution was added the solid product from Example 5 (437 mg, 1.19 mmol) followed by the dropwise addition of triethylamine (240 mg, 2.37 mmol). The ice bath was removed and the reaction was stirred for 1.5 hours. The solution was filtered and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and chromatographed on a silica gel column with a chloroform-ethyl acetate gradient as eluant to give the title product, 525 mg (83%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[C:4]=2[C:5](Cl)=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.CCOCC>[Br:1][C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[C:4]=2[C:5]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1ccc2sc3c(Br)cnc(Cl)c3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncc(Br)c3sc4ccc(Cl)cc4c23)cc1
Reaction time: 0.05 h

Procedure:
A mixture containing 4-bromo-1,8-dichloro[1]benzothieno[3,2-c]pyridine-4-methoxybenzylamine (5 equiv), K2CO3 (4.0 equiv) in DMF (0.2 M) was placed in a microwave reactor at 200° C. for 3.3 min. The reaction was diluted with EtOAc and ether and washed with H2O. The organic solvents were separated and evaporated. The desired product was purified by flash chromatography (10% EtOAc in hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:45][CH2:44][C:43]3[CH:46]=[CH:47][C:40]([CH3:39])=[CH:41][CH:42]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2ccc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and p-methylbenzylamine.