Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([C:10]([OH:12])=O)=[CH:8][C:7]([Cl:13])=[C:6]([CH3:14])[N:5]=1.[C:15]([Cl:20])(=O)[C:16](Cl)=O.[OH2:21]>O1CCCC1>[Cl:13][C:7]1[C:6]([CH3:14])=[N:5][C:4]2[O:21][CH:9]([CH2:16][CH2:15][Cl:20])[CH2:4][N:5]([CH3:6])[C:10](=[O:12])[C:9]=2[CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O
Reactant: Cc1nc(Cl)c(C(=O)O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2c(cc1Cl)C(=O)N(C)CC(CCCl)O2
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 30 %

Procedure:
To a suspension of 29.6 g of 60% sodium hydride (0.74 mole) in 300 ml of tetrahydrofuran under a nitrogen blanket and at reflux was added dropwise at a rate to maintain good reflux a solution of 74.5 g (0.36 mole) of 2,5-dichloro-6-methyl-3-pyridinecarboxylic acid and 36.5 g (0.36 mole) of N-methylpyrrolidinol in 300 ml of tetrahydrofuran. The mixture was heated at reflux for 2 hr and cooled to 15° C. To the mixture was added dropwise, carefully, 47.2 of oxalyl chloride between 15°-20° C. The mixture was stirred at room temperature for 1.5 hr followed by addition of 400 ml of water. Stirring was continued for 10 minutes. Tetrahydrofuran was removed by rotary evaporation and the remaining aqueous extracted with 3×200 ml of toluene. The combined organic layers were washed with 300 ml of water, dried over sodium sulfate, filtered, charcoaled, and concentrated by rotary evaporation. The residue was crystallized from isopropyl alochol/isopropyl ether to give 33 g (30%) of crystals. A 3 g sample was recrystallized from isopropyl ether to give an analytically pure sample, m.p. 65°-69° C.
Reaction SMILES: [NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:38]1[CH:48]=[CH:47][C:41]2[N:42]([CH3:46])[C:43](=[O:45])[S:44][C:40]=2[CH:39]=1>>[NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:38]2[CH:48]=[CH:47][C:41]3[N:42]([CH3:46])[C:43](=[O:45])[S:44][C:40]=3[CH:39]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Reactant: Cn1c(=O)sc2cc(Br)ccc21
Product: Cn1c(=O)sc2cc(-c3ccc(C[C@H](NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)C(N)=O)cc3)ccc21

Procedure:
The subtitle compound was prepared by the method of Example 96 step (a) using (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate and 6-bromo-3-methylbenzo[d]thiazol-2(3H)-one.
Reaction SMILES: C[O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Se](=O)=O.[O:15]1CCOC[CH2:16]1>O>[OH2:2].[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([CH:3]=[O:2])=[O:5]
Reactant: COCC(=O)c1ccccc1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Product: COc1ccccc1C(=O)C=O

Procedure:
A mixture of 3 g of 2-methoxyacetophenone, 2.9 g of selenium dioxide, 20 ml of dioxane and 2 ml of water is treated in the same manner as described in Example 5-(1). 2.9 g of 2-methoxyphenylglyoxal hydrate are thereby obtained as a crude oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:6]([C:7]#[CH:8])[O:5][C:4](=[O:9])[NH:3]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19](I)[CH:20]=2)[N:15]=[CH:14][N:13]=1.C(NC(C)C)(C)C>C1COCC1.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.[Cu](I)I>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:8]#[C:7][CH:6]3[O:5][C:4](=[O:9])[NH:3][C:2]3([CH3:10])[CH3:1])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: C#CC1OC(=O)NC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(C)NC(=O)OC1C#Cc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of 4,4-Dimethyl-5-ethynyl-2-oxazolidinone (1.10 g, 7.90 mmol), 4-chloro-6-iodoquinazoline (1.63 g, 5.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (200 mg, 0.28 mmol), copper iodide (53 mg, 0.28 mmol), and diisopropylamine (0.57 g, 5.60 mmol) in anhydrous THF (30 mL) was stirred at room temperature under nitrogen for 4 hours. After concentration, the residue was dissolved in CH2Cl2 (80 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 50-70% EtOAc in hexane afforded 1.22 g (72%) of yellow solid: 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.53 (s, 3H), 5.14 (s, 1H), 5.57 (br s, 1H), 7.95 (dd, 1H), 8.04 (d, 1H, J=8.8 Hz), 8.38 (d, 1H, J=2.0 Hz), 9.05 (s, 1H).
Reaction SMILES: C([O:4][C:5](=[O:25])[C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH3:20])[C:13]2=[O:21])[C:9]([F:22])=[CH:8][C:7]=1[C:23]#[N:24])(C)C.[OH-].[Na+]>CO.O>[C:23]([C:7]1[CH:8]=[C:9]([F:22])[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH3:20])[C:13]2=[O:21])=[CH:11][C:6]=1[C:5]([OH:25])=[O:4])#[N:24]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(C#N)cc2F)c(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(=O)n(-c2cc(C(=O)O)c(C#N)cc2F)c(=O)n1C
Reaction time: 23 h

Procedure:
A solution of 30.5 g of 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid isopropyl ester (see Example 1) in 150 ml of methanol is maintained at 1°-3° C. for 15 minutes with 4.0 g of sodium hydroxide in 50 ml of water and then stirred for 23 hours. The solution is substantially concentrated by evaporation under reduced pressure and the residue is adjusted to a pH value of 2 with 2N hydrochloric acid. The resulting precipitate is filtered off with suction and subsequently washed with n-hexane to yield 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid, m.p. 232° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=[S:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Product: CCOC(=O)CC1(C)C(=S)Nc2cccc([N+](=O)[O-])c21

Procedure:
A mixture of (±)-ethyl (3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (1.08 g, 3.88 mmol, described in Intermediate 17) and Lawesson's reagent (942 mg, 2.33 mmol) was heated at reflux in xylenes (30 mL) for 90 min. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 90:10, to give the title compound. MS: m/z=295 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=4)[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CN(C=O)C>[CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=4)[CH2:20][NH:21][S:32]([CH3:31])(=[O:34])=[O:33])[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1ncc2cnc3[nH]c(-c4cccc(CN)c4)cc3c21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2cnc3[nH]c(-c4cccc(CNS(C)(=O)=O)c4)cc3c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a flask was added (3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)methanamine (0.075 g, 0.27 mmol, Example #T.3.1), DMF (2.7 mL), DIEA (0.118 mL, 0.676 mmol) and MsCl (0.025 mL, 0.325 mmol). The mixture was stirred at rt for about 10 min. The mixture was purified directly by flash chromatography (25 g silica gel column, DCM/MeOH 1:0 to 10:1 with 2% 2.0 M NH3 in EtOH). The solid was dried under reduced pressure at about 60° C. for about 1 h to give N-(3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)benzyl)methanesulfonamide (0.057 g, 58%): LC/MS (Table 2, Method a) Rt=1.84 min; MS m/z 356 (M+H)+. Syk IC50=B.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1.[CH3:19][C:20]([CH3:46])([O:22][C:23]([NH:25][C:26]([CH3:45])([CH3:44])[C:27]([NH:29][C@H:30]([CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])=[O:24])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:10]3([CH2:11][CH2:12][N:13]([C:31]([C@H:30]([NH:29][C:27](=[O:28])[C:26]([NH:25][C:23]([O:22][C:20]([CH3:46])([CH3:21])[CH3:19])=[O:24])([CH3:45])[CH3:44])[CH2:34][C:35]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[NH:37][CH:36]=4)=[O:32])[CH2:14][CH2:15]3)[CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1ccc2c(c1)C(=O)CC1(CCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1)O2

Procedure:
Prepared by the procedure described in Example 3, Step B. 3,4-Dihydro-6-methylspiro[2H-1-benzopyran-2,4'-piperidine]-4-one hydrochloride (20 mg, 0.058 mmol), (Hashigaki et al Chem. Pharm. Bull. 32 pg 3561-3568 (1984)) α(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid) (32 mg, 0.082 mmol), HOBT (1 eq.), N-methyl morpholine (0.03 mL, 0.28 mmol), and EDC (40 mg, 0.21 mmol). Reaction time: 8 hours. Yield: 34 mg (86%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[N:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH3:28][C:29](N=C(N(C)C)N(C)C)([CH3:31])[CH3:30].BrCC(C)C>C(#N)C.CO>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]3[N:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nn1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Solvent: CO
Product: COc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nn1
Temperature: 20 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-[6-(methyloxy)-3-pyridazinyl]benzenesulfonamide (16 mg, 0.041 mmol) in acetonitrile (1 mL) stirred at room temperature was added N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (7.02 mg, 0.041 mmol). The reaction mixture was stirred at 20° C. for 1 hour, then 1-bromo-2-methylpropane (8.91 μL, 0.082 mmol) was added. The reaction was heated by microwaves to 150° C. for 15 minutes. After cooling, the reaction mixture was diluted with methanol and passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge followed by a sulphonic acid (SCX) SPE cartridge, eluting with methanol. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the crude product. The crude was purified by mass directed autoprep (formic acid modifier), to provide the title compound (1.0 mg). LCMS (2 min, formic) Rt 1.27 min, m/z (ES+) 447 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH3:28].N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: CCCBr
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(Cl)c1
Agent: N
Product: CCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (21 mg, 65%) from (7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 1-bromopropane (30 mg, 0.24 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.92 (t, J=7.3 Hz, 3H), 1.61-1.75 (m, 2H), 2.02-2.35 (m, 6H), 2.45-2.63 (m, 3H), 2.75 (t, J=6.5 Hz, 2H), 2.87-2.98 (br, 1H), 3.00-3.08 (br, 1H), 3.30 (dt, J=10.6, 4.0 Hz, 1H), 3.35-3.48 (m, 2H), 6.94 (s, 1H), 6.99 (s, 1H), 7.21-7.25 (m, 1H), 7.44 (d, J=1.5 Hz, 1H) ppm. MS (CI, NH3): 401.1 (base, M+H).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([O-:16])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>>[N+:18]([C:21]([CH3:22])=[CH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:16][CH3:13])([O-:20])=[O:19]
Reactant: CC(=O)[O-]
Reactant: O=Cc1cccc2ccccc12
Reactant: CC[N+](=O)[O-]
Agent: [NH4+]
Product: COc1ccc2ccccc2c1C=C(C)[N+](=O)[O-]
Yield: 95 %

Procedure:
2.13 g (11.20×10-3 mol) of naphthaldehyde, 30 cm3 of nitroethane and 0.54 g (7×10-3 mol) of ammonium acetate are introduced into a round-bottomed flask. The mixture is stirred and heated to reflux for 2 hours. The nitroethane is then evaporated off under reduced pressure, the residue is taken up with CH2Cl2 and water is added to hydrolyze the acetate. After separation of the two phases, the organic phase is washed with water, the aqueous phases with CH2Cl2 (twice). The organic phase is then dried over MgSO4 and concentrated under reduced pressure 2 59 g (10.64×10-3 mol) of the expected nitroethylenic compound (yellow solid) are then obtained, equivalent to a 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([CH2:8][NH:9][C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:6][CH:7]=1.[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31][N:9]([CH2:8][C:5]1[C:4]([CH3:19])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[C:10]([CH3:11])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:18]
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cc(Cl)cnc1CNC(C)(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(Cl)cc1C)C(C)(C)c1ccccn1

Procedure:
Using General Procedure A: Reaction of (5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amine in CH3CN with 2-bromomethyl-5-cyano-benzoic acid methyl ester, KI, and DIPEA gave 2-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a pale yellow solid. 1H NMR (CDCl3) δ 1.60 (s, 6H), 2.17 (s, 3H), 3.80 (s, 2H), 3.91 (s, 3H), 4.24 (s, 2H), 7.10-7.12 (m, 2H), 7.47 (d, 1H, J=6.0 Hz), 7.63-7.65 (m, 1H), 7.77 (d, 2H, J=9.0 Hz), 7.88 (s, 1H), 8.03-8.09 (m, 2H), 8.56-8.57 (m, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]1[O:10][C@@H:9]1[CH2:11]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:7]([CH2:11][C@@H:9]1[CH2:8][O:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of phenol (9.4 g, 100 mmol) and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (25.9 g, 100 mmol) in 500 mL of acetone was treated with 3 equivalents of potassium carbonate (41.5 g, 300 mmol) and stirred at reflux for 1 day. The suspension was cooled to ambient temperature; the solid was filtered; and the filtrate was concentrated to dryness. The residue was partitioned between methylene chloride and water. The aqueous layer was extracted with CH2Cl2. The organic layers were combined and dried over MgSO4 and concentrated to give the title compound (15.0 g, 99%) as an orange oil; 1H NMR (300 MHz, CDCl3) δ 2.76 (dd, J=4.9, 2.6 Hz, 1H), 2.90 (dd, J=4.9, 4.9 Hz, 1H), 3.30-3.40 (m, 1H), 3.95 (dd, J=11.0, 5.4 Hz, 1H), 4.18 (dd, J=11.0, 3.0 Hz, 1H), 6.85-7.00 (m, 3H), 7.25-7.35 (m, 2H); MS (ES) m/z: 151.0 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][C:8]3[CH2:17][CH2:16][CH:15]([N:18]([C:22]4[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=4)[CH2:19][C:20]#[CH:21])[C:9]=3[CH:10]=2)[N:5]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][CH2:3][C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][C:8]3[CH2:17][CH2:16][CH:15]([N:18]([C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=4)[CH2:19][C:20]#[CH:21])[C:9]=3[CH:10]=2)[N:5]=1
Reactant: C#CCN(c1ccc(C(=O)OC(C)(C)C)cc1)C1CCc2cc3nc(COC)[nH]c(=O)c3cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(COC)[nH]c(=O)c3cc21

Procedure:
A solution of tert-butyl 4-{N-[(6RS)-2-methoxymethyl-4-oxo-3,4,7,8-tetra-hydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoate (0.069 g, 0.15 mmol) in dichloromethane (1 ml) and trifluoroacetic acid (3 ml) was stirred at room temperature for 1 hour and 10 min, then the solvents were removed in vacuo. The residue was triturated with diethyl ether and the precipitate was collected by filtration, washed with diethyl ether and dried in vacuo over P2O5 to afford the title compound as the tifluoroacetate salt: 0.061 g, m.p. 225° C. (dec); 1H-NMR (250 MHz, DMSO-d6, TMS) 2.23, 2.53 (obscured by DMSO peak) (2×m, each 1H, 7-H), 2.90-3.20 (m, 3H, C≡CH, 8-H), 3.34 (s (obscured by the H2O peak), 3H, OCH3), 3.97 (ABq, J=18.0 Hz, 2H, CH2C≡C), 4.32 (s, 2H, 2-CH2), 5.79 (t, J=8.1 Hz, 1H, 6-H), 7.03 (d, J=9.02 Hz, 2H, 3′, 5′-H), 7.58, (s, 1H, 9-H), 7.81 (m, 3H, 5-H, 2′, 6′-H), 12.17 (s, 1H, N3-H); MS (ESI, m/z) 426 {(M+Na)+, 25%}, 404 {(M+H)+, 70%}.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH2:12])[S:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][S:20]([CH3:19])(=[O:22])=[O:21])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: NCc1nc2cc(Br)cnc2s1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCc1nc2cc(Br)cnc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a cooled (ice-water) solution of (6-bromothiazolo[5,4-b]pyridin-2-yl)methanamine (800 mg, 3.28 mmol) and pyridine (800 mg, 9.85 mmol) in CH2Cl2 (10 mL) is slowly added methanesulfonyl chloride (380 mg, 3.28) and stirred at room temperature for 3 hours. Reaction mixture is washed with water (2×10 mL) dried over Na2SO4 and concentrated. Obtained crude product purified on silica gel column using 0 to 5% methanol/CH2Cl2 to give the title compound (800 mg): m/z (Cl) M+2 324.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]1[N:12]=[C:13]([CH2:16][C:17]([CH3:19])=O)[S:14][CH:15]=1.[NH2:20]/[C:21](/[CH3:25])=[CH:22]\[C:23]#[N:24]>C(O)(C)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:16]([C:13]2[S:14][CH:15]=[C:11]([CH3:10])[N:12]=2)=[C:17]([CH3:19])[NH:20][C:21]([CH3:25])=[C:22]1[C:23]#[N:24]
Reactant: C/C(N)=C/C#N
Reactant: O=Cc1ccccc1Br
Reactant: CC(=O)Cc1nc(C)cs1
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2ccccc2Br)C(c2nc(C)cs2)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.811 mmol) of 2-bromobenzaldehyde, 126 mg (0.811 mmol) of the compound from example 4A and 67 mg (0.811 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, the crude material is taken up in 5 ml of ethyl acetate, and the precipitated product is then filtered off 190 mg (61% of theory) of the title compound are obtained.
Reaction SMILES: C1(C)C(C(N)=O)=CC=CC=1.C(OC(=O)[NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH:31]([C:35]1[N:44]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:43](=[O:52])[C:42]2[C:37](=[N:38][CH:39]=[CH:40][N:41]=2)[N:36]=1)[CH:32]([CH3:34])[CH3:33])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(C)(C)C>C(O)(C(F)(F)F)=O.O.ClCCl>[NH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:31]([C:35]1[N:44]([CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:43](=[O:52])[C:42]2[C:37](=[N:38][CH:39]=[CH:40][N:41]=2)[N:36]=1)[CH:32]([CH3:34])[CH3:33])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3nccnc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: Cc1ccccc1C(N)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3nccnc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Formula I where R2 and R3 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; R7 is 3-Amino-propyl-; R8 is —C(O)—R9 where R9 is p-Methyl-phenyl-; X and Y are —C═; and W and Z are —N═: The toluamide, {3-[[1-(3-benzyl-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, was then dissolved in TFA/H2O (95/5) (50 mL) and stirred at room temperature for 1 hour, after which it was diluted with dichloromethane, washed with saturated sodium bicarbonate, water and brine, and dried over sodium sulfate. Concentration of the dichloromethane solution gave the title product (±)-N-(3-amino-propyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propyl]-4-methyl-benzamide as a white solid (150 mg, 98.0%). MS (Cl) M/E: 485.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[CH2:12]([Li])[CH2:13][CH2:14]C.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[CH:4]12[O:5][CH:6]1[CH2:12][CH2:13][CH2:14][CH2:3]2.[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C@H:17]2[CH2:18][CH2:19][CH2:13][CH2:12][C@@H:21]2[OH:20])=[CH:10][CH:9]=[N:8]1
Reactant: [Li]CCCC
Reactant: COCCOCn1cccn1
Reactant: C1CCOC1
Product: C1CCC2OC2C1
Product: COCCOCn1nccc1[C@H]1CCCC[C@@H]1O
Yield: 60 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 155b by using the 1-[(2-methoxyethoxy)methyl]-1H-pyrazole (2.00 g, 12.8 mmol) prepared in Example 155a, butyl lithium (2.69 M solution in hexane; 4.76 mL, 12.8 mmol), a boron trifluoride-diethyl ether complex (2.68 mL, 21.3 mmol), cyclohexene oxide (1.05 g, 10.7 mmol) and THF (100 mL), to yield the title compound (1.64 g, 60%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[Cl-].[NH4+]>C1COCC1>[S:25]([O:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:10]=1)([CH3:24])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Temperature: -50 °C
Yield: 109.5 %

Procedure:
1-[3-[(tert-Butoxycarbonyl)amino]phenyl]methanol (10 g, 44.8 mmoles) (Ref.: F. J. Brown, P. R. Bernstein, L. A. Cronk, D. L. Dosset, K. C. Hebbel. T. P. Maduskuie, Jr., H. S. Shapiro, E. P. Vacek, Y. K. Lee, A. K. Willard, R. D. Krell and D. W. Snyder, J. Med. Chem., 32, 1989, 807-826) and triethylamine (13 g, 17.9 mL, 138.4 mmoles) were dissolved in anhydrous THF (169 mL) and the solution was stirred and cooled to −50° C. Methanesulfonyl chloride (10.26 g, 7.02 mL, 89.6 mmoles) in anhydrous THF (85 mL) was added dropwise over a period of 20 min at −50° C. under an argon atmosphere. The mixture was stirred at −50° C. for an additional 20 min. A saturated aqueous solution of ammonium chloride (12.9 g) was added and the mixture was warmed to 25° C. The mixture was filtered and the filtrate was extracted twice with ethyl acetate. The ethyl acetate was washed with brine, water, dried (MgSO4), filtered and evaporated to dryness to give the title compound (14.78 g). The material was used without further purification.