Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1.C(O)C.C(O)(=O)/C=C/C(O)=O>CS(C)=O>[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[N:20]=[C:21]([CH3:24])[O:22][C:23]5=4)[O:25][CH2:26]3)[CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCC(C(=O)c2ccc(F)cc2)CC1)CO3
Temperature: 80 °C
Yield: 60.9 %

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.45 g, 1.2 mmole) and 4-(4-fluorobenzoyl)piperidine (0.73 g, 3.54 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated to 80° C. under nitrogen for 4 hours. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute 0.28 g of the (S)-enantiomer of the title compound. This was recrystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.30 g of pale yellow solid, m.p. 229-230° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[C:12]([CH:19]=[CH:20][C:21]=2[F:22])[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])=[CH:4][C:3]=1Br.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[C:12]([CH:19]=[CH:20][C:21]=2[F:22])[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])=[CH:4][C:3]=1[C:25]#[C:24][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Nc1ncc(CNc2cc(C(=O)NC3CC3)ccc2F)cc1Br
Reactant: C#Cc1ccccn1
Product: Nc1ncc(CNc2cc(C(=O)NC3CC3)ccc2F)cc1C#Cc1ccccn1

Procedure:
3-((6-amino-5-bromopyridin-3-yl)methylamino)-N-cyclopropyl-4-fluorobenzamide (38 mg, 0.1 mmol) was reacted with 2-ethynylpyridine (0.1 mL) as described in procedure D of Example 5 to afford 3-((6-Amino-5-(2-(pyridin-2-yl)ethynyl)pyridin-3-yl)methylamino)-N-cyclopropyl-4-fluorobenzamide as a solid. It was used without further purification. LC/MS; (M+H)+=402.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.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>[F:10][C:9]([F:12])([F:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[N:22][CH:23]=[C:18]([CH:19]=2)[C:16]([O:15][CH3:14])=[O:17])=[CH:3][CH:4]=1
Reactant: COC(=O)c1cncc(B(O)O)c1
Reactant: FC(F)(F)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cncc(-c2ccc(CC(F)(F)F)cc2)c1
Reaction time: 0.17 h

Procedure:
A solution of 8.00 g (33.5 mmol) of the compound from Example 40A in toluene (304 ml) was admixed under argon at RT with 10.9 g (50.2 mmol) of the compound from Example 33A in ethanol (100 ml) and 5.10 g (36.8 mmol) of potassium carbonate. After stirring for 10 min, 3.87 g (3.35 mmol) of tetrakis(triphenylphosphine)palladium and then 5.83 g (100 mmol) of potassium fluoride in water (64 ml) were added. The mixture was stirred under reflux for 8 h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1). Yield: 9.20 g (69% of theory, purity 75%)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][C:10]([CH3:15])=[CH:11][C:12](O)=[O:13].O>C(Cl)Cl>[CH3:9][C:10]1([CH3:15])[CH2:11][C:12](=[O:13])[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2]1
Reactant: Oc1cccc(O)c1
Reactant: CC(C)=CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(=O)c2ccc(O)cc2O1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
In a flask were placed 55.1 grams (0.5 mole) of resorcinol and 55.1 grams (0.5 mole) 3,3-dimethylacrylic acid. Then, 150 grams of polyphosphoric acid was added, and a steam bath applied to the flask. A red liquid began to form; the temperature of the reaction mixture quickly rose to 120° C. The flask was stirred for 45 minutes at 110° C., then allowed to cool. The contents were poured into a mixture of 500 milliliters water and 400 milliliters methylene chloride then stirred and filtered. The precipitate was washed several times with portions of methylene chloride, water and toluene. There was obtained 65.8 grams, (68% of theoretical yield) 2,2-dimethyl-7-hydroxy-4-chromanone, m.p. 170°-174° C.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:31]([OH:46])[CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)C1C=CC=CC=1>C(O)C.[Pd]>[C:42]([NH:41][C:39]([C@@H:34]1[CH2:35][CH2:36][CH2:37][CH2:38][N:33]1[CH2:32][C@@H:31]([OH:46])[C@@H:30]([NH:29][C:27](=[O:28])[C@H:22]([CH2:23][C:24](=[O:26])[NH2:25])[NH:21][C:19]([C:10]1[C:9]([OH:8])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:20])[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc2ccccc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc2ccccc2cc1O
Yield: 69.4 %

Procedure:
A solution of 181 mg of 1-[3(S)-[[N-(3-benzyloxy-2-naphthoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide in 5 ml of ethanol washydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated. After trituration with diethyl ether there were obtained 110 mg of N-tert.butyl-1-[3(S)-[[N-(3-hydroxy-2-naphthoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-2(S)-piperidinecarboxamide as a pale yellow solid: MS: m/e 632 [M+H]+.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:21](COCC[Si](C)(C)C)[C:20]3[C:19](=[O:30])[N:18]([CH2:31][CH2:32][CH3:33])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C>[CH2:31]([N:18]1[C:19](=[O:30])[C:20]2[NH:21][C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)=[N:14][C:15]=2[N:16]=[CH:17]1)[CH2:32][CH3:33]
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCn1cnc2nc(-c3cn[nH]c3)[nH]c2c1=O
Yield: 36.7 %

Procedure:
A mixture of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.1 g, 0.201 mmol), Pd (OH)2 (20%) (0.2 g), in ethanol (4 ml) and cyclohexene were stirred under nitrogen balloon for 25 hrs. Reaction mixture was filtered through celite bed washed with methanol (20 ml). The filtrate was concentrated under vacuum and the crude product was purified by column chromatography using silica gel (100-200 mesh) and 5 to 6% methanol in DCM as an eluent to obtain 1-propyl-8-(1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one (0.018 g, 24%) as white solid.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:31]3[CH:30]=[N:29][C:28]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)=[N:27][C:26]=3[N:25]([C:42]34[CH2:46][CH:44]([CH2:45]3)[CH2:43]4)[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:31]3[CH:30]=[N:29][C:28]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)=[N:27][C:26]=3[N:25]([C:42]34[CH2:45][CH:44]([CH2:43]3)[CH2:46]4)[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1
Reactant: COc1ccc(CNc2ncc3c(C(=O)c4cncc(N=C(c5ccccc5)c5ccccc5)c4)cn(C45CC(C4)C5)c3n2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncc3c(C(=O)c4cncc(N)c4)cn(C45CC(C4)C5)c3n2)cc1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of [5-(Benzhydrylidene-amino)-pyridin-3-yl]-[7-bicyclo[1.1.1]pent-1-yl-2-(4-methoxy-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-methanone (Preparation 286, 475 mg, 0.78 mmol) in THF (15 mL), citric acid (15 mL of a 1N aq. solution) was added at room temperature and the reaction mixture stirred for 2 hours. The reaction was then quenched with sat. aq. Na2CO3 solution and extracted with EtOAc (2×25 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography on neutral alumina (Methanol:DCM 3:97) to afford the title compound as a pale yellow solid in 92% yield, 320 mg.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([N:19]4[CH2:23][CH2:22][C@@:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20]4)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])(=[O:35])C.[NH4+].CS(C)=O.C1(O)C=CC=CC=1.NC1C=CC=CC=1>O>[OH:35][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([N:19]4[CH2:23][CH2:22][C@@:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20]4)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccc(F)nc5)cc4)CC3)C2)c2ccccc21
Agent: [NH4+]
Solvent: Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccc(O)nc5)cc4)CC3)C2)c2ccccc21
Temperature: 100 °C

Procedure:
A mixture of (1R)-1′-({1-[4-(6-fluoropyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (20.0 mg, 0.0000467 mol, see example 250 for the preparation), and ammonium acetate (0.0216 g, 0.000280 mol) in dimethyl sulfoxide (0.5 mL, 0.007 mol) and water (0.1 mL) was heated at 100° C. in a sealed tube overnight. The major product was the phenol rather than the aniline derivative. The product was isolated and purified by prep-HPLC. LC-MS: 427.2 (M+H+)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH:10]([NH:18][C:19]([C:21]1([NH:36]C(=O)OC(C)(C)C)[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1>C(Cl)Cl>[NH2:36][C:21]1([C:19]([NH:18][CH:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:9][NH2:8])=[O:20])[CH2:22][CH2:23][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CN)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.4 %

Procedure:
Trifluoroacetic acid (3 mL) was added to tert-butyl 4-(2-amino-1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 6) (0.514 g) in DCM (100 mL) at 25° C. The resulting solution was stirred at 25° C. for 3 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness. This material was then further purified by flash silica chromatography, elution gradient 0 to 10% methanolic ammonia (7N) in DCM. Pure fractions were evaporated to dryness to afford 4-amino-N-(2-amino-1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a colourless gum (0.047 g, 11.4%).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:6]=[C:5]([CH:23]2[N:27]=[N:26][C:25](=[O:28])[O:24]2)[CH:4]=1>O1CCOCC1>[ClH:2].[NH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:7]2[CH:6]=[C:5]([CH:23]3[O:24][C:25](=[O:28])[N:26]=[N:27]3)[CH:4]=[C:3]([Cl:2])[N:8]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C3N=NC(=O)O3)cc(Cl)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2cc(C3N=NC(=O)O3)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 188.1 %

Procedure:
4 N Hydrochloric acid in dioxane (3 ml) was added to tert-butyl 1-[6-chloro-4-(5-oxo-2,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-2-yl]piperidin-4-ylcarbamate (Intermediate 50, 0.12 mg, 0.32 mmol). The mixture was stirred at room temperature for 45 min, then concentrated in vacuo to afford the title compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:12]([O:15][CH2:16][CH:17]([CH2:28][O:29][NH2:30])[O:18][CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])(=[O:14])[CH3:13].C(N(CC)CC)C>O1CCOCC1>[C:12]([O:15][CH2:16][CH:17]([O:18][CH2:19][P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])[CH2:28][O:29][NH:30][C:6]1[N:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[NH:8][CH:9]=[O:10])(=[O:14])[CH3:13]
Reactant: O=CNc1c(Cl)ncnc1Cl
Reactant: CCOP(=O)(COC(CON)COC(C)=O)OCC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOP(=O)(COC(CONc1ncnc(Cl)c1NC=O)COC(C)=O)OCC
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A mixture of 4,6-dichloro-5-formamidopyrimidine (0.77 g, 4.0 mmol), diethyl [2-acetoxy-1-(aminooxymethyl)ethoxy]methylphosphonate (1.2 g, 4.0 mmol) and triethylamine (0.82 ml, 6 mmol) in dry dioxan (20 ml) was heated at 100° C. for 2 hours. The reaction mixture was cooled, filtered, and the filtrate evaporated to leave an oil which was chromatographed on silica gel (eluant dichloromethane:methanol 97:3) and gave the title compound as a yellow oil (1.08 g, 60%). 1H NMR: δH [(CD3)2SO] 1.23 (6H,t, J=7 Hz, (OCH2CH3)2), 2.03 (3H,s, COCH3), 3.85-4.35 (11H,m, (OCH2CH3)2 +OCH2P+OCH2CHCH2O). m/z: observed 454.1020; C15H24N4O8PCl (M+) requires 454.0996.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:39])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36](O)=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:41].C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[C:36]([C:21]1[C:22]2[NH:23][C:24]3[C:29]([C:30]=2[C:18]([C:14]2[C:13]([CH3:39])=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:17]=[CH:16][CH:15]=2)=[CH:19][N:20]=1)=[CH:28][CH:27]=[C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])[CH:25]=3)(=[O:37])[NH2:41]
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(=O)O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Reactant: [NH4+]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
A mixture of 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.237 g, 0.451 mmol), ammonium chloride (0.096 g, 1.804 mmol), N,N-diisopropylamine (0.378 mL, 2.165 mmol), BOP (0.259 g, 0.586 mmol), and N-methylmorpholine (0.193 mL, 1.759 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 1.5 hr. To the reaction mixture was added water (30 mL), and the resulting mixture was stirred at room temperature for 30 min. The insoluble product (0.226 g, 0.431 mmol, 96% yield) was collected as a beige solid by suction filtration and dried over Drierite under vacuum.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[CH3:12][C:13]([CH3:18])([CH3:17])[CH:14]([NH2:16])[CH3:15]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:16][CH:14]([CH3:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[S:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(N)C(C)(C)C
Reactant: N#Cc1ccc(N=C=S)cc1
Solvent: C1CCOC1
Product: CC(NC(=S)Nc1ccc(C#N)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 4-cyanophenyl isothiocyanate (2.00 g, 12.5 mmol) in THF (50 mL) at room temperature was added a solution of (±) 3,3-dimethyl-2-aminobutane (2.00 mL, 14.5 mmol) in THF (12 mL) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 3.12 g (96%) of 1-(4-cyanophenyl)-3-(1,2,2-trimethyl-propyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: [Br-:1].[NH2:2][C:3]1[CH:8]=[CH:7][N+:6]([CH2:9][C:10]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]3[C:11]=2[N:12]=[C:13]([O:25]C)[C:14]([O:23]C)=[N:15]3)=[CH:5][CH:4]=1.Br>C(O)(=O)C.C(OCC)C>[Br-:1].[N+:20]([C:18]1[CH:17]=[C:16]2[C:11]([NH:12][C:13](=[O:25])[C:14](=[O:23])[NH:15]2)=[C:10]([CH2:9][N+:6]2[CH:5]=[CH:4][C:3]([NH2:2])=[CH:8][CH:7]=2)[CH:19]=1)([O-:22])=[O:21]
Reactant: COc1nc2cc([N+](=O)[O-])cc(C[n+]3ccc(N)cc3)c2nc1OC
Agent: Br
Agent: [Br-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1cc[n+](Cc2cc([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c23)cc1
Reaction time: 0.17 h

Procedure:
212 mg (0.5 mmol) of 4-amino-1-(2,3-dimethoxy-7-nitro-quinoxalin-5-yl methyl)-pyridinium bromide are stirred in 3 ml of a 48% solution of hydrogen bromide in glacial acetic acid for 18 hours at room temperature. The brownish reaction mixture is diluted with 7 ml of diethyl ether and then stirred for 10 minutes. The resulting solid is filtered off, washed with a small amount of diethyl ether and dried. The title compound is obtained in the form of a yellow solid having a melting point of>245° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.51 g (29.6 mmol) of 3-bromo-4-methylaniline were dissolved in 127 ml of dichloromethane, 6.18 g (29.6 mmol) of 3-(trifluoromethyl)benzoyl chloride and 4.54 ml (32.6 mmol) of triethylamine were added and the mixture was stirred at RT for 30 min. All volatile components were removed under reduced pressure and the residue was suspended in 50 ml of methanol. The solid was filtered off and the filtrate was stirred into 100 ml of 1 M hydrochloric acid. The precipitate formed was filtered off, washed with water and dried. This gave 7.05 g (90% pure, 60% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][CH:22]=[O:23])[C@H:4]1[S:3]2.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][CH:22]=[O:23])[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]1S2
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]1S2
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenyl-2-formyloxyacetamido)penam-3-carboxylate (1.52 g.) in dimethylformamide (7.5 ml.) were added acetic acid (2.3 ml.) and zinc powder (1.8 g.) under ice-cooling, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 to the distillation of ethyl acetate to give oily 2-methyl-2,3-methylene-6-(2-phenyl-2-formyloxyacetamido)penam-3-carboxylic acid (1.1 g.).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH2:13][CH:14]([NH2:17])[CH2:15][NH2:16])=[CH:10][CH:9]=[CH:8]2)[CH3:2].[C:18](O)(=O)C.C(N)=N>CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH2:13][CH:14]1[CH2:15][NH:16][CH:18]=[N:17]1)=[CH:10][CH:9]=[CH:8]2)[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1cccc2cccc(CC(N)CN)c12
Agent: N=CN
Solvent: CCO
Product: CCc1cccc2cccc(CC3CNC=N3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
A solution of 3-(8-ethyl-naphthalen-1-yl)-propane-1,2-diamine (60 mg) in EtOH (6 ml) was treated at r.t. under an argon atmosphere with formamidine acetate (30 mg). The reaction mixture was stirred at r.t. overnight, then concentrated. The crude product was purified by column chromatography (silica gel; eluent: CH2Cl2→CH2Cl2/MeOH 9:1) to give (RS)-4-(8-ethyl-naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole (38 mg) as light yellow gum. MS (ISP): 239.3 ((M+H)+).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[NH:3][C:2]1=[O:9].C(=O)([O-])[O-].[K+].[K+].[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[S:17]>CC(C)=O>[CH2:19]([O:18][P:16]([O:9][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=1)([O:21][CH2:22][CH3:23])=[S:17])[CH3:20]
Reactant: CCOP(=S)(Cl)OCC
Reactant: O=c1[nH]c2c(s1)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)CCC2

Procedure:
A mixture of 21 g of 2,3,5,6,-tetrahydro-4H-cyclopentathiazoline-2-one, 21 g of potassium carbonate and 300 ml of acetone was refluxed for 1 hour and after the addition of 28 g of O,O-diethyl chlorothiophosphate thereto, the mixture was refluxed for 1 hour. The mineral salts were filtered off and the filtrate was distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate to obtain 4g of 2-(diethoxythiophosphoryloxy)-5,6-dihydro-4H-cyclopentathiazole with a refractive index of nD28 = 1.5348.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[O:21])C=CC=CC=1.N>C1COCC1>[C:15]1([CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][C:9]2=[O:21])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1C(Cc2ccccc2)CCCN1Cc1ccccc1
Agent: N
Solvent: C1CCOC1
Product: O=C1NCCCC1Cc1ccccc1
Reaction time: 0.25 h
Yield: 146.9 %

Procedure:
A solution of 1,3-diphenylmethyl-2-piperidinone (2.79 g, 10 mmol) in dry THF (25 mL) was added at -78° C. to a well stirred solution of Li metal (0.70 g, 100 mmol) in liquid NH3 (200 mL). After 15 min, the cooling bath was removed, and the NH3 was allowed to escape (ca. 2 h). The resulting colorless residue was treated with saturated NH4Cl (50 mL), and extracted with EtOAc (3×50 mL). The combined organic extract was washed with brine (25 mL), dried over MgSO4, and concentrated in vacuo to give 2.78 g of brown viscous residue. Flash chromatography over silica gel (1% MeOH in CHCl3 -EtOAc, 1:1) afforded the lactam (See: Rodrequez M, Heitz A, Martinez J (1992) supra)(0.87 g, 46% ) as a colorless solid: mp 120-122° C. (CH2Cl2 -hexanes).