Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11](Cl)[C:10]([CH:14]=[CH2:15])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:23](P(C(C)(C)C)C(C)(C)C)(C)(C)[CH3:24].B1(C=C)OB(C=C)OB(C=C)O1.C1C=CN=CC=1>O1CCOCC1>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([CH:23]=[CH2:24])[C:10]([CH:14]=[CH2:15])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: C=Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=Cc1cc(C(=O)OC(C)(C)C)cnc1C=C
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-6-vinyl-nicotinic acid tert.-butyl ester (2.0 g), Cs2CO3 (3.4 g), tri(tert.-butyl)phosphine (0.04 eq.), tris(dibenzylidenacetone)dipalladium (0.02 eq.), and 2,4,6-trivinylcyclotriboroxane pyridine complex (2.0 g) in dioxane (30 mL) is degassed and heated at 100° C. for 15 h. The mixture is cooled to rt, and diluted with ether (200 mL). The mixture is extracted with 1M aq. NaOH (2×50 mL) and brine (50 mL). The org. phase is dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, EA-heptane) to give 5,6-divinyl-nicotinic acid tert.-butyl ester (0.89 g) as an oil. LC-MS: tR=1.01 min, [M+1]+=232.04.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1/[CH:11]=[CH:12]/[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(Cl)Cl.[H][H]>CO.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: Cn1c(/C=C/c2ccc(C#N)cc2)cc2ccccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cn1c(CCc2ccc(C#N)cc2)cc2ccccc21

Procedure:
2.3 g (8.9 mmol) of (E)-4-[2-(1-methyl-indol-2-yl)ethenyl]benzonitrile are dissolved in 150 ml methanol and 50 ml methylene chloride and hydrogenated with 0.20 g 10% palladium on charcoal at 3 bar hydrogen pressure. The solvent is distilled off in vacuo, the white residue obtained is washed with a little diethylether and acetone.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:10]=[C:9]([C:11](O)=[O:12])[N:8]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:7]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:10]=[C:9]([C:11]([Cl:3])=[O:12])[N:8]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:7]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
1.5 ml of thionyl chloride and 2 drops of dimethylformamide were added to a mixed solution comprising 1.0 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and 10 ml of toluene, followed by reflux with heating for one hour, and thionyl chloride and toluene were distilled off to obtain crude product of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:19])[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[CH3:20][C@H:21]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:31]3[CH2:33][O:32]3)[CH:28]=2)[C:23](=[O:34])[O:22]1>CCO>[OH:32][CH:31]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:34])[O:22][C@@H:21]([CH3:20])[CH2:30]2)[CH2:33][N:8]1[CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4][C:3]1([CH2:2][OH:1])[CH3:19]
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: CC1(CO)CN(C(=O)OCc2ccccc2)CCN1
Solvent: CCO
Product: C[C@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)CC3(C)CO)ccc2C(=O)O1
Temperature: 80 °C

Procedure:
To a solution of racemic benzyl 3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate (1.0 g, 3.8 mmol) (prepared as described in US Patent Application Publication No. US2007/0088039A1, Example 10) in EtOH (13 mL) was added (3S)-3-methyl-6-(oxiran-2-yl)isochroman-1-one (773 mg, 3.80 mmol), the resulting mixture was heated at 80° C. for 16 h, the reaction mixture was concentrated to dryness and purified on silica gel to afford the title compound: LC/MS: m/e 469.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].C([O:24]O)(C)(C)C.C1(C)C=CC=CC=1>CCCCCC.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[V]>[O:24]1[CH2:3][CH:2]1[CH2:1][C:4]1([OH:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: CC(C)(C)OO
Reactant: C=CCC1(O)c2ccccc2CCc2ccccc21
Agent: [V]
Agent: CC(=O)/C=C(/C)O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OC1(CC2CO2)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.6 %

Procedure:
To a stirred, refluxing solution of 35.7 g (0.14 mol) of 5-allyl-5-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene 10 (R. D. Hoffsommer, et al, supra) in 500 ml of hexane was added 0.5 g of vanadium (III) acetylacetonate followed by the dropwise addition of 25.1 g (0.22 mol) of 70% tert-butylhydroperoxide. The resulting yellow mixture was refluxed for 4 hrs., then 100 ml of toluene was added. The reaction was allowed to cool to room temperature and stand for 12 hrs. Excess hydroperoxide was destroyed by the addition of 300 ml of aqueous sodium sulfite (Na2SO3) solution (10%). The organic phase was separated, dried over anhydrous MgSO4, filtered and evaporated. Recrystallization of the solid from CHCl3 -hexane gave 18.5 g (50% yield) of the epoxide 11, m.p. 116°-118° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]#[N:17])[N:10]=[C:9]1[CH:18]([N:22]([CH2:32][CH2:33][NH2:34])[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:36]1([C:41](N)=[NH:42])C=CC=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]#[N:17])[N:10]=[C:9]1[CH:18]([N:22]([CH2:32][CH2:33][NH:34][C:41]([NH2:42])=[NH:36])[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)n1cccn1
Reactant: Cc1ccc(C(=O)N(CCN)C(c2nc(C#N)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N(CCNC(=N)N)C(c2nc(C#N)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To a solution of N-[1-(1-benzyl-4-cyano-5-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-N-(2-amino-ethyl)-4-methyl-benzamide (75 mg, 0.16 mMol) in DMF (1.5 mL) was added 1H-pyrazole-1-carboxamidine hydrochloride (25 mg, 0.17 mMol) and diisopropylethyl amine (57 μL, 0.33 mMol). The reaction was stirred at RT for 16 h, quenched with water (2 mL) and diluted with methylene chloride (2 mL). The aqueous layer was adjusted to pH 7 and extracted with methylene chloride (2×5 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated. Purification of the residue by reverse phase HPLC furnished the title compound (38 mg, 37%) as a white powder. MS (ES) m/e 500.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a pink solid (389 mg).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][C:11]([CH3:21])([CH3:20])[O:12][CH2:13]4.[CH2:22](Br)[CH:23]=[CH2:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:24]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[CH2:10][C:11]([CH3:21])([CH3:20])[O:12][CH2:13]3)[CH:23]=[CH2:22]
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CC(C)(C)OC3
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CC[C@]23COC(C)(C)C[C@H]2[C@H]1Cc1ccc(OC)cc13

Procedure:
A mixture of 3-methoxy-7,7-dimethyl-6-oxamorphinan (XI, prepared in Example 3) (0.005 m), allyl bromide (0.006 m) and potassium carbonate (2 g) in 20 ml of acetonitrile is heated at reflux for 18 hours. The mixture is filtered and the filtrate concentrated. The residue is treated with water and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([S:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:16]2[CH:15]=[N:14]1.Cl[C:30]1[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:36]([C:33]1[CH:32]=[N:31][C:30]([N:26]2[CH2:25][CH2:24][CH:23]([S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]4[N:13]([C:4]5[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=5[F:2])[N:14]=[CH:15][C:16]=34)[CH2:28][CH2:27]2)=[N:35][CH:34]=1)[CH3:37]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCc1cnc(N2CCC(Sc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)nc1
Temperature: 150 °C
Yield: 34.8 %

Procedure:
A mixture of 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (250 mg, 0.56 mmol), 2-chloro-5-ethyl-pyrimidine (680 μL, 5.6 mmol), and triethylamine (315 μL, 2.24 mmol) in isopropanol (4 mL) was heated under microwave irradiation for 15 min at 150° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound A237 as a white solid (100 mg, 35%). 1H NMR (CDCl3, 400MHz) δ 1.18 (t, 3H), 1.82-1.94 (m, 2H), 2.28-2.37 (m, 2H), 2.53 (q, 2M), 3.06 (s, 3H), 3.55-3.64 (m, 2H), 4.41-4.55 (m, 3H), 7.82 (m, 3H), 8.24 (s, 1H), 8.37 (s, 2H), 8.74 (s, 1H). Exact mass calculated for C23H24FN7O2S2 513.61, found 514.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:17]([O-:19])=[O:18])=[C:9]([OH:13])[CH:8]=1
Reactant: Oc1cccc(OCc2cccc(F)c2)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
1.0 g (5 mmol) of 3-(3-fluoro-benzyloxy)-phenol is dissolved in 10 ml acetic acid and cooled to 10°. 0.44 g (5 mmol) of 65% nitric acid is dissolved in 10 ml acetic acid and slowly added to the previous solution. The colored mixture is stirred for 15 min. at 10° and for 2 h at room temperature. 50 ml of water is added and the product extracted 3 times with ethyl acetate. Chromatography (silica gel, dichloromethane/methanol 98:2) yields 0.38 g (32%) of the desired product as a yellow solid. MS: m/e=262.1 (M+−H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][C:33]([NH2:35])=[S:34])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:42][C:43]([O:45][CH2:46][C:47]1[CH2:56][S:55][C@@H:50]2[C@H:51]([NH2:54])[C:52](=[O:53])[N:49]2[C:48]=1[C:57]([OH:59])=[O:58])=[O:44]>C(Cl)Cl>[C:43]([O:45][CH2:46][C:47]1[CH2:56][S:55][C@@H:50]2[CH:51]([NH:54][C:27](=[O:29])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][C:33]([NH2:35])=[S:34])[C:52](=[O:53])[N:49]2[C:48]=1[C:57]([OH:59])=[O:58])(=[O:44])[CH3:42]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=S)CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(N)=S)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C

Procedure:
A solution of 0.5 g of dicyclohexyldicarbodiimide in 5 ml of methylene chloride was added to a solution of 1.01 g of the product of Step A, 2 ml of pyridine and 0.656 g of 7-amino-cephalosporanic acid and the mixture was stirred at room temperature to effect precipitation and was vacuum filtered. The product was rinsed with methylene chloride and dried to remove about 0.5 g of dicyclohexylurea. The filtrate was poured into 25 ml of hydrochloric acid and the mixture was stirred for 5 minutes. The decanted organic phase was washed with 25 ml of water and was dried and vacuum filtered. The filtrate was evaporated to dryness and the residue was taken up in isopropyl ether. Efflorescence occured and the mixture was vacuum filtered. The recovered product was rinsed and was dissolved in 4 ml of ethyl acetate 0.18 g of activated carbon were added thereto and the mixture was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was stirred while 20 ml of isopropyl ether were added over 5 minutes. The mixture was stirred another 5 minutes and was vacuum filtered. The recovered product was rinsed with isopropyl ether and was dried to obtain the syn isomer of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-amino-2-thioxoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C1C[O:26][CH2:25]C1.C([Li])CCC.CN(C)C=O>CCCCCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:25]=[O:26])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To stirred solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (10.0 g, 0.0309 mol;) in THF (400 mL, 5 mol) at −78° C. was added 2.5 M of n-Butyllithium in hexane (18 mL). The solution was stirred at −78° C. for 30 minutes. N,N-Dimethylformamide (5.3 mL, 0.068 mol) was added and stirring continued at −78° C. for 1 hours. The reaction was slowly quenched using 0.1N HCl cold solution. The product was extracted with DCM. The organic extracts were combined, washed with brine, filtered, and concentrated to dryness to give 2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-8-carbaldehyde (10.76 g, 99%) as a yellow solid. The crude was carried on without further purification.
Reaction SMILES: CN1CCOCC1.Cl[C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([S:15]([O:18][C:19]2[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([CH3:25])[CH:24]=2)(=[O:17])=[O:16])[CH:14]=1>[Pd].CO>[CH3:28][O:27][C:12]1[CH:11]=[CH:10][CH:9]=[CH:14][C:13]=1[S:15]([O:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([CH3:25])[CH:24]=1)(=[O:16])=[O:17]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: [Pd]
Solvent: CO
Solvent: CN1CCOCC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Yield: 63 %

Procedure:
4-Methylmorpholine (3.2 mL, 29.1 mmol) was added to a mixture of 3-(5-chloro-2- methoxyphenylsulfonyloxy)-5-methylphenol (8.82 g, 26.8 mmol, as prepared in the preceding step) and 10% palladium on carbon (2.23 g) in deoxygenated methanol (15 mL). The mixture was hydrogenated (atmospheric pressure) at ambient temperature for 3 h then filtered through Celite with methanol. Solvent was removed in vacuo and the crude product was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound (4.97 g, 63%) as a colorless syrup. 1H-NMR (300 MHz, DMSO-d,) δ 9.71 (s, 1 H), 7.76 (ddd, 1 H, J=1.7, 7.4, 8.4 Hz), 7.69 (dd, 1 H, J=1.7, 7.9 Hz), 7.38 (d, 1 H, J=8.4 Hz), 7.09 (dt, 1 H, J=1.0, 7.9 Hz), 6.48 (br s, 1 H), 6.33 (br s, 1 H), 6.26 (t, 1 H, J=2.2 Hz), 4.00 (s, 3 H), 2.15 (s, 3 H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C14H14O5S: 317.0 (M+Na). Found: 316.9
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2.[CH2:15]=[O:16].S(=O)(=O)(O)O.C1N2CN3CN(C2)CN1C3>Cl.ClCCl>[CH3:1][O:2][C:3]1[C:12]2[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8][C:7]=2[C:6]([CH:15]=[O:16])=[CH:5][CH:4]=1
Reactant: COc1cccc2ccc(=O)n(C)c12
Reactant: C=O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(C=O)c2ccc(=O)n(C)c12
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 57.8 %

Procedure:
8-Methoxy-1-methyl-1H-quinolin-2-one (21.14 g, 0.11 mol) and paraformaldehyde (10.6 g) were suspended in concentrated hydrochloric acid (105 ml), and 4 ml of concentrated sulfuric acid was added, followed by stirring at 70 to 80° C. for 2.5 hours. After cooling to room temperature, ice water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was dissolved in 400 ml of chloroform, and hexamethylenetetramine (4.25 g, 0.03 mol) was added, followed by heating under reflux for 2.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. 50% acetic acid (110 ml) was added to the residue, and stirring was carried out at 100° C. for 2 hours. After cooling to room temperature, water was added, and the insoluble matter was collected by filtration and dried to thereby obtain 13.81 g (yield: 57%) of 8-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-5-carboxaldehyde as a light yellow powder.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:6]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:27]4\[NH:21][C:22](=[O:23])[NH:24][C:25]\4=[O:26])=[C:9]3[N:8]=[C:7]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CNC(=O)N1
Reactant: COC(=O)Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)Nc1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Temperature: 80 °C
Yield: 35 %

Procedure:
To methyl 7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylcarbamate (33 mg, 0.12 mmol) in 1.0 mL ethanol was added hydantoin (12 mg, 0.12 mmol) and piperidine (11 ul). The reaction was heated at 80° C. for two hours. The reaction was cooled to room temperature, the yellow precipitate was filtered, and washed with ethanol to yield 15 mg (40% yield) (Z)-methyl 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylcarbamate. LCMS (M+1=358)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.F[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:47][CH3:48])[CH:43]=2)[C:38]=1[CH:49]=[O:50]>O1CCCC1.ClCCl.[Cl-].[NH4+]>[C:1]([O:5][C:6](=[O:23])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:49]2[O:50][C:30]3[C:31](=[CH:32][CH:33]=[C:34]([F:36])[CH:35]=3)[C:37]3[C:38]2=[C:39]2[C:44](=[CH:45][CH:46]=3)[CH:43]=[C:42]([O:47][CH3:48])[CH:41]=[CH:40]2)=[CH:18][CH:17]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C=O)c(-c3ccc(F)cc3F)ccc2c1
Reactant: CC(C)(C)OC(=O)N(CCN1CCCCC1)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c3c(ccc2c1)-c1ccc(F)cc1OC3c1ccc(N(CCN2CCCCC2)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Dissolve (4-bromo-phenyl)-(2-piperidin-1-yl-ethyl)-carbamic acid tert-butyl ester in dry tetrahydrofuran (20 mL). Cool to −78° C. and add 1.6 M n-butyl lithium in hexanes (0.79 mL). After 30 minutes, add 2-(2,4-difluoro-phenyl)-6-methoxy-naphthalene-1-carbaldehyde (0.25 g, 0.839 mmol) and stir 45 minutes cold. Warm to room temperature over 1 hour. Reflux 2 hrs. Cool to room temperature and dilute with dichloromethane (20 mL) and saturated aqueous ammonium chloride (20 mL). Separate the organic layer and wash the aqueous layer twice with dichloromethane. Combine the organics and dry over magnesium sulfate. Filter and concentrate in vacuo. Purify the residue by column chromatography using a silica gel column eluting with a linear gradient beginning with dichloromethane and ending with 4:1 dichloromethane methanol to give 0.45 g (92%) of the title compound: mass spectrum (ion spray) m/z=583.3 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:10]([NH:20][CH:21]2[CH2:23][CH2:22]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][C:34](=[O:35])[N:20]([C@H:10]2[C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH:21]2[CH2:22][CH2:23]2)=[CH:38][CH:39]=1
Reactant: Clc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2NC2CC2)cc1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc(F)cc1)N(C1CC1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A mixture of 2.27 g (6.94 mmol) rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl-amine, 987 mg (7.64 mmol) DIPEA, 8.48 mg (0.07 mmol) DMAP and 1.27 g (7.29 mmol) 4-fluorophenyl chloroformate in 40 mL DCM at 0° C. was stirred at room temperature over night and evaporated to dryness. the residue was purified by column chromatography on silica eluting with a gradient formed from TBME and heptane. The product containing fractions were evaporated to yield 1.64 g (51%) of the title compound as colorless viscous oil. MS m/e: 465.1 [M+H]+.