Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[C:5]([CH:9]2[N:14]3[C:13]4[N:12]([C:23](=[O:24])[NH:20][C:18](=[O:19])[C:17]=4[CH:16]=[N:15]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1cnn2c1NCCC2c1cccc(C(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)CC2

Procedure:
To a 3.0 g portion of 4,5,6,7-tetrahydro-7-(3-(trifluoromethyl)phenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 13) suspended in 40 ml of dry tetrahydrofuran is added portionwise under nitrogen 8.0 g of 1,1'-carbonyldiimidazole and 60 ml of dry tetrahydrofuran. The reaction mixture is heated at reflux for 96 hours, and then is cooled to give a white precipitate which is collected by filtration. The precipitate is treated with 10 ml of water, filtered and dried to give 1.05 g of the desired product as a white solid, mp 297-300° C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[CH:10][C:9]1=2.Cl>O.C(O)C.CN(C)C=O>[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]2[CH:13]=[C:12]([S:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=3)=[O:2])[CH:11]=[CH:10][C:9]1=2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)CCC(C)(C)c2cc(SCc3ccc(C(=O)O)cc3)ccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(S(=O)Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A solution of 3.4 g (16 mmol) of sodium periodate in 30 ml of water was added dropwise to 5.3 g (15 mmol) of the thioether from Example 10 in a mixture of 150 ml of ethanol and 40 ml of dimethylformamide at 0° C., and the mixture was then stirred at the same temperature for 2 hours and at room temperature overnight. The reaction solution was then poured into water, the pH was adjusted to 5 with 2N hydrochloric acid, the mixture was extracted with dichloromethane, and the organic extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. Crystallization of the oily residue from ethanol yielded 2.2 g of title compound of melting point 198°-200° C.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:12][C:13](O)=[O:14])[C:8]2[C:3]1=[N:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:6][CH:7]=2.Cl.CN.[CH3:25][N:26]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C)C=O>[CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([NH:26][CH3:25])=[O:14])[C:8]2[C:3]1=[N:4][C:5]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[N:6][CH:7]=2
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cn1c(=O)n(CC(=O)O)c2cnc(-c3ccccc3)nc21
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)ncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of 8,9-dihydro-9-methyl-8-oxo-2-phenyl-7H-purin-7-acetic acid (9.1 g) obtained in Example 48-(2), methylamine hydrochloride (3.2 g), BOP reagent (21.2 g), triethylamine (9.7 g), and dimethylformamide (100 ml) is stirred at room temperature for two hours. Water is added to the reaction mixture, and the precipitates are collected by filtration, and washed with water to give crude 8,9-dihydro-9-methyl-N-methyl-8-oxo-2-phenyl-7H-purin-7-acetamide (8.1 g).
Reaction SMILES: Cl[CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C:26]([O-:29])(=[O:28])[CH3:27].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:26]([O:29][CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)(=[O:28])[CH3:27]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CCl
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
1.0 g of 21-chloro-17-hydroxy-4-pregnene-3,20-dione in 20 ml of dimethylformamide is agitated at 80° C. with 1.0 g of potassium acetate. After 30 minutes, the reaction mixture is introduced into ice water, the precipitated product is suctioned off, dissolved in ethyl acetate, and dried over sodium sulfate, thus obtaining 940 mg of 21-acetoxy-17-hydroxy-4-pregnene-3,20-dione; mp 236.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:33][CH2:34]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:34][CH:33]=[C:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC=C(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=O)OCC=C(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
308 mg (0.85 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 348 mg (1.65 mmol) of 3,3-diphenyl-2-propene-1-ol, 260 mg (1.36 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 26 mg (0.21 mmol) of 4-dimethylaminopyridine were stirred together in 10 ml of dichloromethane at room temperature for one hour. Water was added to the reaction liquid. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2OS(C(F)(F)F)(=O)=O)[S:4][C:3]=1[C:19](=[O:21])[NH2:20].[N+:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([O-:24])=[O:23]>O1CCOCC1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[NH:29][C:28]2[CH:30]=[CH:31][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[S:4][C:3]=1[C:19]([NH2:20])=[O:21]
Reactant: NC(=O)c1sc2nccc(OS(=O)(=O)C(F)(F)F)c2c1N
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: NC(=O)c1sc2nccc(Nc3ccc([N+](=O)[O-])cc3)c2c1N
Yield: 11.4 %

Procedure:
A solution of 20 mg trifluoromethanesulfonic acid 3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester (see Example 19) and 40.5 mg 4-nitroaniline in 1 mL of dry dioxane was heated at 95° C. overnight under N2. The reaction was concentrated and applied to a 2 mm silica gel prep plate that was developed twice in 7.5% MeOH—CH2Cl2. The band was eluted with 20% MeOH—CH2Cl2, concentrated in vacuo, re-dissolved in 5% MeOH—CH2Cl2, filtered, concentrated, and dried in vacuo at 60° overnight to get 2.2 mg of the title compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[NH:4][C:3]1=[O:14].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[S:33](Cl)(=[O:35])=[O:34]>>[NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([S:33]([C:25]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[O:23][CH3:22])(=[O:34])=[O:35])[C:3]1=[O:14]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2
Product: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2S(=O)(=O)c1ccc([N+](=O)[O-])cc1OC

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 16 from 3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and 2-methoxy-4-nitrobenzenesulfonyl chloride. Crystallization from a DCM/iso ether mixture gives the expected product, which crystallizes with 0.25 mol of iso ether. M.p.=129°-132° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[CH2:25][CH2:24]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH:7]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[O:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](Cl)=[O:55]>ClCCl>[C:39]([O:38][CH2:37][C:8]1[CH:9]=[C:10]([CH:11]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:7]=1)[O:12][CH2:13][CH2:14][C:15]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([N:29]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[C:54]([C:50]3[O:49][CH:53]=[CH:52][CH:51]=3)=[O:55])[CH2:25][CH2:24]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCN3CCC(Nc4ccc(C)cc4)CC3)CCCCC2)c1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCN3CCC(N(C(=O)c4ccco4)c4ccc(C)cc4)CC3)CCCCC2)c1
Reaction time: 1 h

Procedure:
To a solution of 1,3-diacetoxymethyl-5-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzene (synthesized in Example 33) (222 mg) dissolved in dichloromethane (4 mL) was added triethylamine (0.11 mL). 2-Furoyl chloride (0.06 mL) was added to the solution under ice cooling. The temperature was allowed to rise to room temperature, and the solution was stirred for 1 hour. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, chloroform-methanol (10:1)] to give N-[1-[2-[1-[2-[3,5-bis(acetoxymethyl)phenoxy]ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (276 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH2:20][S:21][CH3:22])=[C:15]([NH:24][CH3:25])[CH:14]=1>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH2:20][S:21]([CH3:22])=[O:6])=[C:15]([NH:24][CH3:25])[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1cc(F)ccc1C(=O)CSC
Solvent: ClCCl
Product: CNc1cc(F)ccc1C(=O)CS(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroperoxybenzoic acid (3.49 g) in dichloromethane (80 ml) was added to a stirred solution of 1-(4-fluoro-2-methylaminophenyl)-2(methylthio)ethanone (4.3 g), prepared in a similar manner to that described in Example 2, in dichloromethane (75 ml) under nitrogen over 15 minutes whilst maintaining the temperature below 25°. The mixture was stirred for a further 2 hours at ambient temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution (3×50 ml) an evaporated in vacuo to give a solid product. Crystallisation from toluene gave 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone, m.p. 137°-138°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([N:29]([CH3:33])[CH2:30][CH2:31][NH2:32])=[CH:24][C:23]=1[Cl:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:32][CH2:31][CH2:30][N:29]([CH3:33])[C:25]3[CH:24]=[C:23]([Cl:34])[C:22]([NH2:21])=[C:27]([Cl:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CN(CCN)c1cc(Cl)c(N)c(Cl)c1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCN(C)c1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, 2-[N-(4-amino-3,5-dichlorophenyl)-methylamino]-ethylamine and triethylamine analogously to Example 6.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:20])[C:8]=1[N:9]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[NH:10][C:11]([O:13][CH3:14])=[O:12].[C:21]1(C)C=CC=CC=1>C(OCC)C>[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:20])[C:8]=1[N:9]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[N:10]([CH3:21])[C:11]([O:13][CH3:14])=[O:12]
Reactant: Cc1ccccc1
Reactant: COCC(=O)N(NC(=O)OC)c1c(C)csc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COCC(=O)N(c1c(C)csc1C)N(C)C(=O)OC

Procedure:
0.73 g (0.03 mol) NaH and 7.95 (0.03 mol) methyl 2-(2,4-dimethylthien-3-yl)-2-(methoxyacetyl)-hydrazinecarboxylate in 100 ml dry toluene are heated under reflux for 3 hours. The reaction mixture is then, together with 9.52 g (0.067 mol) CH3J, transferred into a sealed cylinder and heated 20 hours at 110°. The mixture is, after cooling, diluted with diethylether, washed with water, dried and evaporated to yield the title compound.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH2:31])[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8].Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH:31][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccccn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 120 °C
Yield: 39 %

Procedure:
Sodium tert-butoxide (135 mg, 1.41 mmol)) was added to a suspension of ethyl 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 16) (450 mg, 1.28 mmol), 2-bromopyridine (403 mg, 2.55 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (40 mg, 0.102 mmol) and tris(dibenzyldieneacetone)dipalladium(0) (47 mg, 0.051 mmol) in anhydrous toluene (4.5 mL). The mixture was heated under microwave irradiation to 120° C. for 1 h in a sealed vial. The mixture was partitioned between EtOAc and water, the aqueous layer was extracted twice with EtOAc, the combined organic phases were dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue. The residue was purified by chromatography (10 g column, EtOAc/cyclohexane gradient followed by MeOH/EtOAc gradient) to give ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (216 mg, 0.503 mmol, 39% yield) as a brown gum. LCMS: (Formate, 2 min), Rt=0.84 min, MH+430.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6](/[CH:7]=[CH:8]/[C:9]2[S:13][C:12]([C:14]3[CH:22]=[CH:21][C:17]([N:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=3)=[N:11][CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:20][N:18]([CH3:19])[C:17]1[CH:16]=[CH:15][C:14]([C:12]2[S:13][C:9](/[CH:8]=[CH:7]/[C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:24][CH:23]=3)=[CH:10][N:11]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(/C=C/c2cnc(-c3ccc(N(C)C)cc3)s2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)c1ccc(-c2ncc(/C=C/c3ccc(O)cc3)s2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 10 mL round bottomed flask equipped with a magnetic stir bar containing DCM (5 mL) was placed 264 (0.1 g, 0.3 mmol), the reaction mixture was cooled to 0° C., BBr3 (0.8 mL of 1M in DCM) was added drop wise and was stirred at RT for 3 hrs. The reaction was neutralized with sat. NaHCO3, extracted into DCM (3×15 mL). The combined organic extracts were washed with water (15 mL), brine (15 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified over silica gel using THF:Hexanes (3:2) as an eluent to afford UG-4-69 (0.01 g, 10%) as a white solid.
Reaction SMILES: [CH2:1]([S:5][C:6]([CH3:35])([CH3:34])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH:12]([CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]1)[C:13]([S:16]CC1C=CC(OC)=CC=1)([CH3:15])[CH3:14])[CH2:2][CH2:3][CH3:4].FC(F)(F)S(O)(=O)=O.O1CCCC1.Cl.O1CCOCC1>CCOCC>[CH2:1]([S:5][C:6]([CH3:34])([CH3:35])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH:12]([CH2:26][N:27]1[CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH2:32]1)[C:13]([SH:16])([CH3:15])[CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSC(C)(C)CNCCNC(CN1CCC(C)CC1)C(C)(C)SCc1ccc(OC)cc1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCSC(C)(C)CNCCNC(CN1CCC(C)CC1)C(C)(C)S
Yield: 29.5 %

Procedure:
A solution of Compound (32) (HCl salt) (2.5 g; 4.2 mmol) in a 1M trifluoromethanesulfonic acid in tetrahydrofuran (42 ml; 42 mmol) was stirred for 1 hour under cooling. The reaction mixture was combined with ether and extracted with 2N hydrochloric acid five times. The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with chloroform three times. The chloroform extract was washed with a saturated aqueous sodium chloride solution two times, dried over anhydrous sodium sulfate and concentrated. Under cooling, a 4N hydrogen chloride in dioxane (7 ml; 28 mmol) was added thereto, followed by concentration. The residue was purified by silica gel column chromatography with a mixture of chloroform and methanol (20:1) as an eluting solvent to give Compound (33) (HCl salt) (0.5 g; yield, 24%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[K+]>C(O)COCCO>[CH2:4]([C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH2:1])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NN=C(c1ccccc1)c1ccccc1N
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccccc1Cc1ccccc1

Procedure:
In the manner given in Preparation 11, 2-aminobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 2-benzylaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
The mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (130 mg, 0.32 mmol), tert-butyl 4-aminobenzoate (185 mg, 0.96 mmol), EDC (122 mg, 0.64 mmol) and DMAP (78 mg, 0.64 mmol) in 10 mL of DMF was stirred at room temperature for 2 hours. Excess of DMF was removed under reduced pressure and the residue was dissolved in 100 mL of ethyl acetate, washed with brine (2×10 mL), dried over anhydrous sodium sulfate. The crude residue was purified by silica gel chromatography (200-300 mesh, eluting with ethyl acetate) to give tert-butyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)benzoate (130 mg, 70%) as a white solid. 1H NMR (300 MHz, DMSO): δ 10.76 (s, 1H), 10.18 (s, 1H), 9.41 (s, 1H), 8.97 (s, 1H), 8.62 (d, 1H, J=8.1 Hz), 8.10 (d, 1H, J=7.8 Hz), 7.95 (s, 4H), 7.85 (s, 1H), 7.71 (t, 1H, J=7.7 Hz), 7.54 (dd, 1H, J1=9.0 Hz, J2=2.4 Hz), 6.99 (d, 1H, J=9.0 Hz), 3.81 (s, 3H), 3.75 (s, 3H), 1.57 (s, 3H). LC-MS: 584 [M+H]+, tR=1.78 min. HPLC: 98.03% at 214 nm, 98.38% at 254 nm, tR=7.05 min.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]2[N:16]([CH3:17])[CH:15]=[CH:14][C:9]2=[N:10][C:11]=1[C:12]#[N:13].[BH4-].[Na+]>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]2[N:16]([CH3:17])[CH:15]=[CH:14][C:9]2=[N:10][C:11]=1[CH:12]([NH2:13])[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: Cn1ccc2nc(C#N)c(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(N)c1nc2ccn(C)c2cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Ethylmagnesium bromide (4.18 mL, 12.54 mmol) was added to a stirred solution of 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (740 mg, 3.13 mmol) in THF (16 mL) at room temperature. The mixture was stirred for one hour at room temperature and then quenched with methanol (5 mL). Sodium borohydride (237 mg, 6.27 mmol) was added. The reaction mixture was stirred for one hour, quenched with 1N HCl (1.5 mL) and stirred for 20 minutes. Next, the mixture was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2×). The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound as a tan oil (680 mg, 81%). ESI-MS m/z [M+H]+ calc'd for C11H14BrN3, 268. found 268.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:22](OCC)(=[O:24])[CH3:23]>>[C:22]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)=[O:13])(=[O:24])[CH3:23]
Reactant: COc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CCOC(C)=O
Product: COc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methoxypyridine-2-carbonyl)indole (Example 72). m.p.: 207-208° C. (ethyl acetate)
Reaction SMILES: C(O)C.C([O:6][C:7](=O)[CH2:8][CH2:9][N:10]([C:18]1[C:23]([NH2:24])=[CH:22][N:21]=[C:20]([Cl:25])[N:19]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1([CH3:17])[CH3:16])C>C(O)(=O)C>[Cl:25][C:20]1[N:21]=[CH:22][C:23]2[NH:24][C:7](=[O:6])[CH2:8][CH2:9][N:10]([CH:11]3[CH2:15][CH2:14][CH2:13][C:12]3([CH3:17])[CH3:16])[C:18]=2[N:19]=1
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCCC1(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CCCC1N1CCC(=O)Nc2cnc(Cl)nc21
Yield: 74 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 2.5 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-59) prepared in the previous step was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, and then water and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 1.6 g of (rac)-2-chloro-9-(2,2-dimethyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-59).