Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([I:9])=[CH:7][CH:6]=[CH:5][N:4]=1.ClC1C(C[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:28]=[CH2:29])[C:19](=[O:21])[CH3:20])=CC(F)=C(Cl)N=1>>[I:9][C:8]1[C:3]([CH2:2][N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:28]=[CH2:29])[C:19](=[O:21])[CH3:20])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ncccc1I
Reactant: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Product: C=Cc1ccccc1N(Cc1ncccc1I)C(C)=O
Yield: 70 %

Procedure:
Compound 51C (8.5 mg, 70%) was prepared from bb (5.2 mg, 0.032 mmol) and 51B (9.7 mg, 0.33 mmol) by a route analogous to that used for the preparation of 1C. HPLC Rt=2.929 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=[C:20]([Br:24])[Br:21])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of triphenylphosphine (119.6 g) in methylene chloride (420 mL) at 0° C. was added a solution of carbon tetrabromide (75.72 g) in methylene chloride (90 mL). After completion of the addition, the mixture was stirred for 10 min. Then a solution of 3-(benzyloxy)benzaldehyde (J.A.C.S., 99, 2571 (1977)) (40 g) in methylene chloride (150 ml) was added. The mixture was stirred for 16 hrs at -5° C. After warming to room temperature, the organic layer was washed with saturated sodium bicarbonate (2×150 ml) and brine (1×150 ml), then dried over magnesium sulfate, filtered and the mixture was concentrated. Ether (300 ml) was added, causing the formation of a precipitate which was filtered. The filtrate was concentrated and the process repeated 2 times. Finally, the filtrate was concentrated and chromatographed using 10% ethyl acetate in hexane, affording the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.C1COCC1.Cl[S:46]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])(=[O:48])=[O:47]>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:46]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])(=[O:48])=[O:47])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: CCOC(=O)CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)(=O)N1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C

Procedure:
To a 25-mL one-neck round bottom flask with stir bar was added 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (0.1 g, 0.209 mmol), pyridine (0.02 mL; 0.247 mmol) and THF (3 mL) at 0° C. To the resulting solution was added a solution of ethyl 2-(chlorosulfonyl)acetate (43 mg; 0.23 mmol) in dichloromethane (1 mL) over 10 min. The reaction was then warmed to room temperature. The reaction was quenched with 1N HCl (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM and the organics were concentrated. The resulting residue was purified by silica gel column chromatography (0-10% MeOH/DCM) to yield ethyl 2-((4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)sulfonyl)acetate as an orange oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[CH:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCC(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 12 h
Yield: 46.1 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.1 g) in methylene chloride (20 ml) was slowly added under ice cooling a solution of optically active 1,1,1-trifluoro-2-octanol (0.74 g, [α]D20 =+25.2) and triethylamine (0.4 g) in methylene chloride (10 ml). After the solution was left to stand to reach room temperature, it was stirred for 12 hours. The solution was poured in ice water and was extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in the order, and dehydrated over anhydrous magnesium sulfate. The solution was distilled under reduced pressure to remove the solvent until a crude product was obtained. The product was subjected to silica-gel column chromatography to obtain 1,1,1-trifluoro-2-octyl 4-benzyloxybenzoate (0.73 g).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f16) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:12]([CH2:17][CH2:18]Br)[C:13]([O:15][CH3:16])=[O:14].O>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2([C:13]([O:15][CH3:16])=[O:14])[CH2:18][CH2:17]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(Br)CCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C1(n2cc([N+](=O)[O-])cn2)CC1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (3.0 g) in N,N-dimethylacetamide (30 mL) was added sodium hydride (60% in mineral oil, 1.2 g) in an ice bath, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added methyl 2,4-dibromobutanoate (6.9 g) in an ice bath, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16]2.C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16]2)=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCC2=O)c1cc(Cl)ccc1Cl
Yield: 18 %

Procedure:
Reaction of 2,5dichlorobenzoic acid (287 mg, 1.50 mmol) in thionyl chloride (3.5 mL) then with 5-amino-indan-1-one (74 mg, 0.50 mmol) in presence of triethylamine (0.5 mL) in THF (6 mL) according to method B gave 2,5-dichloro-N-(1-oxo-indan-5-yl)-benzamide (33 mg, 0.09 mmol, 35% yield) as a green powder after purification by chromatography on silica gel (eluent: DCM).
Reaction SMILES: [OH-].[Na+].[N:3]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[CH:4]1>O.C(O)C>[N:3]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[CH:4]1
Reactant: CCOC(=O)CCCCCn1cnc2cnc3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (1.66 g, 41.7 mmol) in water (15 mL) was added to a solution of ethyl 6-(1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (10.0 g, 32.1 mmol, prepared in Part A of Example 10) in ethanol (75 mL), and the reaction was stirred at ambient temperature for two hours and then concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 5 with the addition of 10% hydrochloric acid. The mixture was extracted with dichloromethane, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.5 g of 6-(1H-imidazo[4,5-c]quinolin-1-yl)hexanoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[O:19][CH2:20][CH2:21][CH:22]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CSc1nc(N)nc(C2=CCCO2)c1C#N
Temperature: 100 °C
Yield: 48.5 %

Procedure:
To a stirred solution of 700 mg (2.86 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 25 ml dry dioxane under argon at room temperature were added 1.13 g (3.14 mmol) tributyl-(4,5-dihydro-furan-2-yl)-stannane and 281 mg (0.40 mmol) bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/1) afforded 325 mg (49%) 2-amino-4-(4,5-dihydro-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow crystalline solid. ES-MS m/e (%): 257 (M+Na+, 47), 235 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([Br:12])[CH3:11])([O-:3])=[O:2].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[BrH:12].[C:14]([S:15][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:11])(=[NH:13])[NH2:16]
Reactant: NC(N)=S
Reactant: CC(Br)c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: Br
Product: CC(SC(=N)N)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 33.5 g of 1-(2-nitrophenyl)ethyl bromide and 11.4 g of thiourea in 375 ml absolute ethanol was stirred at reflux temperature for 31/2 hours. The reaction mixture was allowed to cool to room temperature and was concentrated to one-half volume in vacuo. The solution was then cooled to ca. -60° C. and 1-chlorobutane was added until a gummy solid formed. The supernatant was decanted and the residue dried in vacuo to give 38 g of 1-(2-nitrophenyl)ethyl carbamimidothioate hydrobromide as a light orange solid which was not further purified.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:10]=[C:11]([S:14][CH3:15])[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:24])=[O:5])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:10]=[C:11]([S:14]([CH3:15])=[O:32])[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (138 mg, 0.40 mmol) was dissolved in CH2Cl2 (6 mL) and 2-benzenesulfonyl-3-phenyl-oxaziridine (155 mg, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then the solvent was removed under reduced pressure and the remaining residue was purified by prepative TLC (50% ethyl acetate/hexane). The more polar, product-containing, reaction was extracted into CH2Cl2 and the solvent evaporated to provide 8-cyclopentyl-2-methanesulfinyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a white solid (110 mg, 75.7%). M++1: Calc'd. 364.4. Found 364.2.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:34]([OH:36])=[O:35])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(OCC=C)=O)=[CH:23][CH:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C@@H:19]([C:34]([OH:36])=[O:35])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])=[CH:26][CH:25]=1
Reactant: C=CCOC(=O)Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A 500 mL cylindrical glass vessel equipped with a coarse glass frit was charged with N-[(9H-fluoren-9-ylmethoxy)carbonyl]-4-[[(2-propenyloxy)carbonyl]amino]-L-phenylalanine substituted Wang resin (10 g, 7.5 mmol) obtained from Example 61 and a solution prepared from bis(triphenylphosphine)palladium dichloride (1.6 g, 2.3 mmol) and acetic acid (5 mL, 83 mmol) in dried dichloromethane (150 mL). The resulting mixture was agitated for 30 minutes followed by the addition of tri-n-butyl tin hydride (20 mL, 74.3 mmol). The resulting mixture was agitated for 1 hr. To the mixture was added tri-n-butyl tin hydride (10 mL, 37 mmol). Agitation was continued for 1 hour and the mixture was filtered. To the resulting resin was added a solution prepared from bis(triphenylphosphine)palladium dichloride (1.6 g, 2.3 mmol) and acetic acid (5 mL, 83 mmol) in dry dichloromethane (150 mL). The mixture was agitated for 30 minutes followed by the addition of tri-n-butyl tin hydride (20 mL, 74.3 mmol). The resulting mixture was agitated 1 hour. To the mixture was added additional tri-n-butyl tin hydride (10 mL, 37.15 mmol). Agitation was continued for 1 hour. After the second deprotection cycle, the mixture was washed with dichloromethane (2×100 mL), methanol (2×100 mL) and dimethylformamide (2×100 mL) to give 4-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin suitable for use in subsequent steps.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])=[CH:20][C:19]=1[F:27]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-(4-chloro-3-fluorophenyl)-boronic acid, (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 96%, 348.0058 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20](OS(C(F)(F)F)(=O)=O)[C:21]3[S:27][CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:15]=[CH:16][CH:17]=1.CN(C=O)C>O>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=3)[C:21]3[S:27][CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: N#CCc1ccc(N)cc1
Reactant: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A 8-mL vial was charged with 2-(4-aminophenyl)acetonitrile (40 mg, 0.3 mmol, 1.25 eq.), [2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate (100 mg, 0.24 mmol, 1. eq.) and DMF (1 ml). The resulting mixture was stirred at 70° C. overnight. After cooling to room temperature, water was added to the mixture (5 ml). The precipitate was collected by filtration and washed with water (20 ml). After drying, the crude product was purified by chromatography on silica gel using hexane/dichloromethane (1:1, 1:1.5 then 1:2) as eluent to give the title compound (35 mg, 37% yield).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:14])[CH:8]=[C:9]([CH:13]=1)C(O)=O)[CH2:2][CH2:3][CH3:4]>N1C2C(=CC=CC=2)C=CC=1.[Cu-]=O>[CH2:1]([C:5]1[NH:6][C:7](=[O:14])[CH:8]=[CH:9][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)O)cc(=O)[nH]1
Agent: O=[Cu-]
Solvent: c1ccc2ncccc2c1
Product: CCCCc1cccc(=O)[nH]1

Procedure:
4.9 g (25 mmol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid are boiled under reflux (237° C.) for 1.5 h with 1.79 g (12.5 mmol) of copper (I) oxide in 50 ml of quinoline. After filtering off, the volatile constituents are removed by distillation in vacuo (110° C. at 17 mbar, then 67° C. at 9 mbar). The residue is chromatographed twice on silica gel using dichloromethane/methanol (40:1)→(20:1) and the product is stirred in petroleum ether.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H][H]>[Pd].C(O)(=O)C>[CH:6]1([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NCC(=O)O
Reactant: [H][H]
Reactant: O=C1CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 108 h
Yield: 91 %

Procedure:
Similar equipment and procedure as described in Example 1 were employed. 75.5 grams glycine (1.01 moles, Aldrich, 99+%), 118.4 grams cyclohexanone (1.21 moles, Aldrich 99.8%), 300 ml glacial acetic acid and 11.2 grams of Pd (5%)/C were used. The reaction was carried out in a 600 ml Parr reactor under 1000 psig (7000 kPa) hydrogen pressure at 75° C. No noticeable hydrogen uptake was noticed after 1.5 days, and the reaction was carried out for 4.5 days. The reactor was opened after cooling to room temperature. The solid catalyst was filtered by suction. The filtrate was evaporated to remove the acetic acid and the excess cyclohexanone. A viscous crude product (brown) remained which started to crystallize upon cooling to room temperature. The crude product was stirred into excess ether whereby a white solid precipitated out. The solid was filtered, washed with ether and dried. The solid was redissolved in a very small amount of acetic acid and recrystallized by adding an appropriate amount of ether. 144.5 grams of white crystals were recovered (91% yield based on glycine). Elemental analysis:calculated: C:61.12; H:9.62; N:8.91; 0:20.36; found:C:60.96; H:9.75; N:8.88; 0:20.41.
Reaction SMILES: O[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.BrN1C(=O)CCC1=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]>C(O)C>[NH:6]1[C:7]2[S:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:2]=2[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: Nc1ccccc1S
Reactant: O=c1[nH]cc(O)c(=O)[nH]1
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Product: O=c1[nH]c2c(c(=O)[nH]1)Nc1ccccc1S2

Procedure:
Then, to a solution or suspension of a 5-hydroxypyrimidine-2,4(1H,3H)-dione derivative of formula (IV) in a reaction inert solvent is added N-bromosuccinimide portion-wise at room temperature. A preferred solvent is ethanol. The reaction mixture is stirred until the derivative of formula (IV) disappears. Then, a 2-aminobenzenethiol derivative of formula (V) is added and the mixture is heated at reflux. Certain 2-aminobenzenethiol derivatives of formula (V) are commercially available and, further, the derivatives of formula (V) can be prepared from the corresponding 2-aminobenzothiazoles by hydrolysis as described by Mital, R. L., et al., J. Chem. Soc. (c), 2148 (1969). When a precipitate results after reflux of the reaction mixture, the precipitate is collected to give a 1,5-dihydro-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione derivative of formula (I). When no precipitate is obtained after reflux, the derivative of formula (I) is obtained by chromatographic separation on silica gel. The foregoing method for reacting derivatives of formula (IV) with derivatives of formula (V) to yield derivatives of formula (I) is analogous to the method described by Sako, M., et al., Chem. Pharm. Bull., 32, 2474 (1984).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[CH3:15].[N:16]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH2:16])=[CH:5][C:4]=1[CH3:15]
Reactant: COC(=O)CNc1ccc(OC)c(C)c1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(N)c1ccc(OC)c(C)c1
Reaction time: 1 h
Yield: 7.5 %

Procedure:
N-(4-methoxy-3-methylphenyl)glycine, methyl ester (Intermediate 96, 5 g, 0.0239 mol) was dissolved in a mixture of glacial acetic acid (45 ml) and water (3 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (1.7 g, 0.0251 mol) in water (5 ml) over 30 minutes and the reaction was stirred for one hour. Zinc dust (6 g, 0.093 mol) was added over 11/2 hours at the same low temperature and stirred at room temperature for 1 hour. The reaction was poured into water (150 ml) and extracted with ethyl acetate (2×100 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased, then dried (MgSO4) and evaporated to give a yellow oil. This was purified by flash column chromatography on silica (Merck 9385; 100 g) eluting with ether-hexane 1:1 to give the title compound as an orange oil (0.4 g, 7%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=3)[NH:15][C:14]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.O=S(Cl)[Cl:28].[CH3:30]O>>[ClH:28].[O:25]=[C:14]1[C:11]2([CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24][CH3:30])=[O:23])[CH:20]=2)[NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1ccc(C(=O)O)cc12
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)c1ccc2c(c1)C1(CCNCC1)C(=O)N2
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 1′-(tert-butoxycarbonyl)-2-oxospiro[indoline-3,4′-piperidine]-5-carboxylic acid (2 g, 6.0 mmol) in methanol (30 mL) was added dropwise SOCl2 (5 mL) at 0° C. Then the reaction mixture was stirred overnight at rt. The reaction mixture was concentrated to give methyl 2-oxospiro[indoline-3,4′-piperidine]-5-carboxylate hydrochloride (1.4 g, 81%), which was used for the next step without purification. 1H NMR (CD3OD): 2.00 (m, 2H), 2.20 (m, 2H), 3.281 (m, 1H), 3.39 (m, 2H), 3.61 (m, 2H), 3.85 (m, 2H), 3.88 (m, 2H), 7.00 (m, 1H), 7.98 (m, 2H).