Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].[CH3:3][N:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C:8](=[N:10][OH:11])[CH3:9].[N+:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)([O-:15])=[O:14].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([O:11][N:10]=[C:8]([CH2:7][CH2:6][CH2:5][N:4]([CH3:12])[CH3:3])[CH3:9])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(CCCN(C)C)=NO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(CCCN(C)C)=NOc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 40.5 %

Procedure:
A suspension of 15.0 gm (82 mMol) potassium hydride (22% dispersion in mineral oil) in 10 mL tetrahydrofuran was cooled in an ice bath. To this suspension was slowly added a solution of 9.8 gm (68 mMol) N,N-dimethyl-5-amino-2-pentanone oxime in 20 mL tetrahydrofuran resulting in vigorous gas evolution. Once this addition was complete, a solution of 12.5 gm (88.3 mMol) 4-nitrofluorobenzene and 0.90 gm (3.4 mMol) 18-crown-6 in 10 mL tetrahydrofuran were added. The dark solution was stirred for 1 hour at ice bath temperature and then for 3 hours at room temperature. The reaction mixture was then poured into 100 mL of aqueous 5% potassium carbonate and the resulting mixture was extracted with dichloromethane. These organic extracts were combined, washed with aqueous 5% potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. The residual oil was subjected to flash silica gel chromatography, eluting with 10% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 7.3 gm (40%) of the desired oxime ether as a dark oil.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:17]([NH2:18])=[C:16]([O:24][CH3:25])[CH:15]=1.Cl[C:27]1[N:32]=[C:31]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH:30]=[CH:29][N:28]=1>CC(O)CCC>[F:13][C:14]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:17]([NH:18][C:27]2[N:32]=[C:31]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[CH:30]=[CH:29][N:28]=2)=[C:16]([O:24][CH3:25])[CH:15]=1
Reactant: Clc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 120 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
p-Toluenesulfonic acid hydrate (225 mg, 1.18 mmol) was added in one portion to a mixture of 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 200 mg, 1.07 mmol) and 3-(2-chloropyrimidin-4-yl)-1H-indole (247 mg, 1.07 mmol) in 2-pentanol (10 mL). The resulting mixture was then stirred at 120° C. for 18 h. The resulting precipitate was collected by filtration, washed with 2-pentanol (5 mL) and dried in vacuo to give a yellow solid. The solid was triturated with CH3CN to give a solid which was collected by filtration and dried in vacuo to give the title compound (224 mg, 55%) as a yellow solid; m/z: ES+ MH+ 380.21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][N:24]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH2:23][N:24]=[C:7]([C:9]3[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=3[F:15])[C:6]=2[CH:17]=1
Reactant: O=C(c1cc(Cl)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F
Agent: NN
Solvent: CCO
Product: Fc1cccc(F)c1C1=NCc2nccn2-c2ccc(Cl)cc21

Procedure:
In the manner given in Example 33, 5-chloro-2',6'-difluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone in ethanol is heated with hydrazine to give 8-chloro-6-(2,6-difluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc3ccccc3n2)cc1

Procedure:
2-(4-Nitrophenoxy)quinoline (3 mmoles, 0.82 g) was dissolved in 100 ml ethyl acetate and hydrogenated over 2.0 g 5% Pd/C at room temperature for 1 hr. The solution was filtered through cellulose and concentrated to yield 2-(4-aminophenoxy)quinoline 0.58, 82%. Mass Spec (FD) 236. Calculated for C15H12N2O: C, 76.25; H, 5.12, N, 11.86. Found: C, 75.97; H, 5.37; N, 11.83.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[Cl:20][C:21]1[C:22]([CH:29]=O)=[N:23][N:24]([CH:26]([F:28])[F:27])[CH:25]=1>>[Cl:20][C:21]1[C:22]([CH2:29][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]3([CH3:18])[C:14]([F:15])([F:16])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]3)[CH:7]=2)=[N:23][N:24]([CH:26]([F:28])[F:27])[CH:25]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: O=Cc1nn(C(F)F)cc1Cl
Product: C[C@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)N=C(N)COCC1(F)F
Yield: 11.4 %

Procedure:
In an analogous manner as described for example 2 the reductive amination of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) (27.3 mg, 100 μmol) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (19.9 mg, 110 μmol) yielded the title compound (5 mg, 11.4%) as a colorless oil. MS (ISP): m/z=438.2 [M+H]+and 440.1 [(M+2+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.CN(C=O)C.C(NC(C)C)(C)C.C[Si](C)(C)[C:41]#[C:42][C:43]1([CH3:47])[CH2:46][O:45][CH2:44]1>[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:47][C:43]1([C:42]#[C:41][C:2]2[CH:3]=[C:4]3[C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[CH:13]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH2:46][O:45][CH2:44]1
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: CC(C)(C)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3(C)COC3)ccc1O2
Temperature: 90 °C

Procedure:
A sealable tube was charged with (S)-7-bromo-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (75 mg, 0.179 mmol), copper iodide (3.38 mg, 0.018 mmol), tetrakis(triphenylphosphine)palladium (20.53 mg, 0.018 mmol). To this mixture was added DMF (355 μL, 0.178 mmol), diisopropylamine (498 μL, 3.55 mmol) and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (90 mg, 0.533 mmol). The tube was flushed with argon, sealed and heated to 90° C. for 12 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-((3-methyloxetan-3-yl)ethynyl)-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:24]=1)[CH3:2].[OH-].[NH4+:33].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(OCC)C>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:33])[C:8]=2[N:24]=1)[CH3:2]
Reactant: CCOCc1nc2c[n+]([O-])c3cc(N4CCOCC4)ccc3c2n1CCCOC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(N4CCOCC4)ccc3c2n1CCCOC(C)C
Reaction time: 24 h

Procedure:
2-Ethoxymethyl-1-(3-isopropoxypropyl)-7-(morpholin-4-yl)-1H-imidazo[4,5-c]quinoline 5-oxide from Part B was dissolved in dichloromethane (4 mL). Ammonium hydroxide (2 mL) was added, followed by p-toluenesulfonyl chloride (0.074 g). The reaction was stirred for 24 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The combined organic fractions were concentrated under reduced pressure to yield a yellow-brown oil. The oil was covered with diethyl ether and a precipitate formed. The solid was recovered by filtration and then dried to provide 0.085 g of 2-ethoxymethyl-1-(3-isopropoxypropyl)-7-(morpholin-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 161-162.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[C:6]1(=[O:11])[CH2:10][CH2:9][CH:8]=[CH:7]1.O>C(Cl)Cl>[N:1]1([CH:8]2[CH2:9][CH2:10][C:6](=[O:11])[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=C1C=CCC1
Solvent: O
Solvent: ClCCl
Product: O=C1CCC(n2cccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A mixture of pyrazole (6.85 g, 100 mmol), 2-cyclopenten-1-one (19.3 g, 235 mmol) and ScCl3 (1.42 g, 9.38 mmol) in anhydrous CH2Cl2 (3 mL) was stirred at room temperature for 30 min. The reaction mixture was poured into water and then extracted with CH2Cl2. The organic layer was washed with brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=4/1) to yield 3-(1H-pyrazol-1-yl)cyclopentan-1-one (14.1 g, 94%) as yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[C:23]#[N:24]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=4)[C:23]#[N:24])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: COc1ccc(CCl)cc1C#N
Product: COc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1C#N
Yield: 72 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 5-(chloromethyl)-2-methoxybenzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 72%) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]2[CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[N:16]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)[N:4]=1.[OH-].[Na+]>C(O)C.O>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]2[CH:14]=[C:15]([C:25]([OH:27])=[O:26])[N:16]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)[N:4]=1
Reactant: COC(=O)c1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 610 mg (1.34 mmol) of methyl 5-(3,5-bistrifluoromethylpyrazol-1-ylmethyl)-2-(3-chloropyridin-2-yl)-2H-pyrazole-3-carboxylate in 9 ml of ethanol is admixed dropwise with a solution of 699 mg (1.78 mmol) of sodium hydroxide in 7 ml of water. The mixture is stirred at room temperature for 2 hours and concentrated to about 5 ml on a rotary evaporator. This residue is admixed with 5 ml of tert-butyl methyl ether and the organic phase is subsequently washed with water. The combined aqueous phases are adjusted to a pH of about 3 with concentrated hydrochloric acid, with ice cooling, and are extracted with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and then the solvent is removed on a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:14][OH:15])([CH2:12][OH:13])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][OH:13])([CH2:14][OH:15])[CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(CO)CO
Solvent: C1CCOC1
Solvent: CO
Product: OCC1(CO)CNc2cc(Cl)ccc21
Temperature: 20 °C
Yield: 92.8 %

Procedure:
A mixture of 6-chloro-3,3-bis-hydroxymethyl-1,3-dihydro-indol-2-one (5.8 mmol), THF (10 mL) and a solution of borane-dimethylsulfide complex in THF (2 M, 30 mL) was heated at 70° C. for 3 h, then cooled to 20° C. MeOH (30 mL) was added dropwise (caution,) over 0.2 h, then mixture was heated at reflux for 2 h. Resulting mixture was cooled then evaporated in vacuo to give an oily residue. Chromatography (SiO2; gradient elution with 20-100% EtOAc in petrol) gave the title compound (1.15 g) as an oil which crystallised. MS: [M+H]+=214.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH:38][C:39]([C:41]3[N:42]([CH2:52][CH3:53])[C:43]4[C:48]([CH:49]=3)=[C:47]([O:50][CH3:51])[CH:46]=[CH:45][CH:44]=4)=[O:40])=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([N:29]2[CH2:30][CH2:31][N:26]([C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:39]([C:41]4[N:42]([CH2:52][CH3:53])[C:43]5[C:48]([CH:49]=4)=[C:47]([O:50][CH3:51])[CH:46]=[CH:45][CH:44]=5)=[O:40])=[CH:36][N:37]=3)[CH2:27][CH2:28]2)=[O:19])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Reactant: CCn1c(C(=O)Nc2ccc(N3CCNCC3)nc2)cc2c(OC)cccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)[C@H]4CC[C@H](C(=O)OCc5ccccc5)CC4)CC3)nc2)cc2c(OC)cccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of trans-cyclohexane-1,4-dicarboxylic acid mono-benzyl ester (50 mg, 0.16 mmol), CH2Cl2 (5 mL), and a catalytic amount of DMF was stirred under Ar, and oxalyl chloride (2M in dichloromethane, 200 μL, 0.4 mmol) was dripped into the mixture over 5 min. The mixture was stirred at room temperature and after 1.0 hr the reaction was concentrated to dryness. Benzene was added and the solution was evaporated to dryness again. The white-yellow solid was re-dissolved in 5 mL of CH2Cl2 and dripped, under Ar, into a solution of 1-ethyl-4-methoxy-1H-indole-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide (60.0 mg, 0.16 mmol), triethylamine (0.41 mg, 0.2 mmol) in 5 mL of CH2Cl2. The reaction was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in 50 mL of EtOAc and washed with 50 mL of saturated ammonium chloride, brine and dried with anhydrous sodium sulfate. The solvent was removed, and the crude product was purified by flash chromatography (hexanes:EtOAc), to afford the product trans-4-(4-{5-[(1-ethyl-4-methoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid benzyl ester (35 mg, 37% yield) as a white solid. LCMS for C36H41N5O5 calcd. (m/e) 623, observed 624 (M+H).
Reaction SMILES: C(OC(=O)[C@H:5]([CH2:7][CH2:8][C:9](OCC)=O)[NH2:6])C.S(Cl)(Cl)=O.Cl.C(OC(=O)[C@H:24](CCC(OCC)=O)[NH2:25])C.[CH2:34]([N:36](CC)[CH2:37]C)C>CN(C)C1C=CN=CC=1>[N:25]1[C:24]2[N:6]=[CH:5][CH:7]=[CH:8][C:9]=2[CH:37]=[N:36][CH:34]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: c1cnc2ncncc2c1

Procedure:
Those compounds of the present invention where R2 is prop-1,3-diyl are prepared by first preparing a benzoic acid derivative described above having a p-propen-1-yl group using the oxazoline described in Meyers, Acc. Chem. Res., 14, 375 (1978), which is incorporated herein by reference. Acid hydrolysis (5N HCl, reflux, 36 hours) affords 4-allylbenzoic acid which is converted to the corresponding diethyl-L-glutamate derivative by initial treatment with thionyl chloride (4.0 eqv., benzene, reflux, 4 hours) followed by diethyl-L-glutamate hydrochloride (2.1 equivalents), 4-dimethylamino-pyridine (0.01 eqv.) and triethylamine (18 hours). Coupling to either the pyrrolo- or pyrido[2,3-d]pyrimidine, at least by Alternative 2, affords the compounds of the present invention where R2 is a propen-1,3-diyl.
Reaction SMILES: [CH2:1]([C:7]1[C:8]([C:21]([OH:23])=[O:22])=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O[C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][N:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:7]1[C:8]([C:21]([O:23][C:25]2[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])=[CH:27][N:26]=2)=[O:22])=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:17])([CH3:18])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(OCc1ccccc1)c1ccc(O)nc1
Reactant: CCCCCCc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCc1cc2c(cc1C(=O)Oc1ccc(C(=O)OCc3ccccc3)cn1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
6 g of 3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carboxylic acid were dissolved in 180 ml of methylene chloride. After the addition of a solution of 4.8 g of benzyl 6-hydroxy-nicotinate in 160 ml of methylene chloride and of 2.3 g of 4-dimethylaminopyridine, the solution was cooled to 0° C. and treated with 4.4 g of dicyclohexylcarbodiimide. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours, thereafter poured into ice-cold aqueous ammonium chloride solution, extracted several times with ether, washed with water, dried over sodium sulfate and evaporated. The crude product, for the most part crystalline, was filtered over silica gel (eluent hexane/ethyl acetate=9:1) and recrystallized from hexane. After repeated crystallization of the mother liquor there were obtained all together 5.7 g of benzyl 6-(3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carbonyloxy)-nicotinate in colorless crystals, m.p. 94°-95° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2.C([SiH](CC)CC)C>ClCCl.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[CH:26][C:18]=3[CH3:17])[NH:22][CH:21]=2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Cc1cccc2[nH]ccc12
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2[nH]cc(Cc3ccc(Br)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
Add TFA (114.4 mmol) to a solution of 4-bromobenzaldehyde (76.2 mmol), 4-methylindole (76.2 mmol), and triethylsilane (228.4 mmol) in dichloromethane (10 mL) pre-cooled in an ice bath. Allow the mixture to warm to room temperature and stir for 2 hours. Add additional triethylsilane (228.4 mmol) and warm the mixture to 30° C. overnight in an oil bath. Dilute the reaction with water (100 mL) and extract with dichloromethane (2×100 mL). Separate and wash the organic phase with water (2×100 mL) and brine (100 mL). Dry the organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography over silica gel (120 g cartridge) eluting with 0-10% ethyl acetate in petroleum ether to yield the title compound (8 g, 26.6 mmol): MS (m/z): 301 (M+1)
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:26][C:12]2([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[N:13]=[C:14]([NH:17]C(=O)C3C=CC=CC=3)[S:15][CH2:16][CH:11]2[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].NN>C(O)C.C(OCC)(=O)C>[Si:1]([O:8][CH:9]1[CH2:26][C:12]2([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[N:13]=[C:14]([NH2:17])[S:15][CH2:16][CH:11]2[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1cccc(-c2cccc(C34CC(O[Si](C)(C)C(C)(C)C)CC3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc(-c2cccc(C34CC(O[Si](C)(C)C(C)(C)C)CC3CSC(N)=N4)c2)c1
Temperature: 120 °C
Yield: 100.3 %

Procedure:
A mixture of N-(6-(tert-butyldimethylsilyloxy)-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.200 g, 0.349 mmol) and hydrazine (0.559 g, 1.75 mmol) in ethanol (4 mL) is stirred at 120° C. over night. The mixture is cooled, diluted with ethyl acetate and is washed with water. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure to give the title compound (0.164 g, 100%). ES/MS m/e: 469 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]=1)[C:7](=[O:15])[C:8]([CH2:12][CH2:13][OH:14])=[C:9]([CH3:11])[N:10]=2.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[OH:14][CH2:13][CH2:12][C:8]1[C:7](=[O:15])[N:6]2[CH:16]=[C:2]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH3:11]
Reactant: Cc1nc2ccc(Br)cn2c(=O)c1CCO
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: Cc1nc2ccc(-c3cccs3)cn2c(=O)c1CCO
Temperature: 130 °C

Procedure:
In a round-bottom flask under a current of argon, mix 5 g of 7-bromo-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 6.2 ml of tributyl-thiophen-2-yl-stannane, 1 g of tetrakis(triphenylphosphine) palladium and 250 ml of N-methylpyrrolidone. Heat the solution at 130° C. for 2 hours and then evaporate off the solvent in vacuo; take up the residue in 200 ml of dichloromethane, wash the solution with 10% potassium fluoride solution, filter, separate off the organic phase and wash it with water. After drying over magnesium sulphate and evaporation, the residue obtained is purified by chromatography on silica gel using a mixture of dichloromethane/methanol: 95/5 as eluant.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([C:16]([OH:20])=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(C(=O)OCc2ccccc2)o1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
490 mg of 5-formylfuran-2-carboxylic acid benzyl ester was dissolved in 10 mL of acetonitrile, and added with a solution containing 413 mg of sulfamic acid in 5 mL of water. After cooling to 0° C., a solution containing 202 mg of sodium chlorite and 232 mg of potassium dihydrogen phosphate in 5 mL of water was added dropwise. After cooling at this temperature for 30 minutes, sodium thiosulfate aqueous solution was added at 0° C. to stop the reaction, and extracted with a mixture of tetrahydrofuran and ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to afford 520 mg of the title compound as white crystals.