Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][CH3:40]>CC(N(C)C)=O>[CH2:37]([N:2]1[CH:3]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:21]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:1]1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCBr
Reactant: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.128 mmol) in dimethylacetamide (1 ml) was added potassium carbonate (265 mg, 0.192 mmol) followed by 1-bromobutane (13 μl, 0.115 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The product was purified by preparatory HPLC to yield the desired product. LCMS: RT: 2.56 min, MI: 446, Method: 2; 1H NMR (DMSO, 300 MHz): 9.42 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 8.25 (s, 1H), 7.64 (d, 2H), 7.57 (d, 1H), 7.40 (dd, 2H), 6.95 (d, 2H), 4.26 (t, 2H), 4.09 (t, 2H), 2.96 (t, 2H), 2.72 (s, 4H), 1.88 (t, 2H), 1.83 (s, 4H), 1.30 (dd, 2H), 0.92 (t, 3H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13]O>C(O)(=O)C.O>[CH2:1]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCSCc1ccccc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=S(CCCCl)Cc1ccccc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
1.2 g of 1-benzylthio-3-chloro-n-propane, synthesized by ◯1 of Synthesis Example 2 was dissolved in 50 ml of acetic acid, and 8.7 g of 35% aqueous hydrogen peroxide was added thereto dropwise under stirring below 10° C. After that, it was warmed gradually to room temperature again, then stirred further for 4 hours. The reaction mixture was poured in 300 ml of iced water, and extracted 2 times by each 150 ml of methylene chloride. The methylene chloride layer was washed 2 times with 5% aqueous solution of sodium hydroxide, followed by water, and dried over anhydrous magnesium sulfate. A colorless solid residue was obtained by distilling off methylene chloride. It was washed by n-hexane to give 12.6 g (yield: 96.9%) of the object 1-benzylsulfinyl-3-chloro-n-propane as a colorless crystal. m.p. 70° to 71° C.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].[Cl:8][C:9]([Cl:14])(Cl)[C:10](Cl)=[O:11]>COCCOC.CCOCC.[Cu].[Zn]>[Cl:8][C:9]1([Cl:14])[C:10](=[O:11])[CH2:4][CH:3]1[CH2:2][C:1]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCC(=O)OC
Agent: [Cu]
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Product: COC(=O)CC1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 47.4 %

Procedure:
To a reaction mixture of methyl but-3-enoate (1.0 g, 10 mmol) and zinc-copper couple (2.0 g, 15.5 mmol) in DME (5 mL) and ether (30 mL) was added trichloroacetyl chloride (2.98 mL, 26.7 mmol) under N2 at rt. The reaction mixture was stirred at rt for 2.5 days. The reaction mixture was filtrated through diatomaceous earth (Celite®) and washed with DCM. The filtrate was concentrated and purified by 80 g silica gel cartridge which was eluted with a 20 min gradient of 0-60% EtOAc in hexane to yield methyl 2-(2,2-dichloro-3-oxocyclobutyl)acetate (1.0 g). 1H NMR (400 MHz, CDCl3) ppm 3.66-3.70 (3H, m), 3.42-3.55 (1H, m), 3.23-3.39 (1H, m), 3.05 (1H, dd, J=17.82, 8.78 Hz), 2.90 (1H, dd, J=16.94, 6.65 Hz), 2.67 (1H, dd, J=16.94, 8.16 Hz).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1.[C:17]([CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])(=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([NH:15][C:17](=[C:20]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH3:18])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: Cc1cc(C)c(-c2ncccc2N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Nc1cccnc1-c1c(C)cc(C)cc1C)=C1CCOC1=O
Yield: 64.4 %

Procedure:
p-Toluenesulfonic acid monohydrate (39 mg, 0.20 mmol) was added to a solution of 2-mesityl-3-pyridinamine (3.9 g, 18 mmol) and α-acetyl-γ-butyrolactone (4.7 g, 37 mmol) in toluene (80 mL). The mixture was heated under reflux for seven days while removing water using Dean-Stark apparatus. The mixture was evaporated, and the resulting crystals were washed with 60% diethyl ether/ethyl acetate, to give the title compound (3.74 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:7]=[C:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C/C(/[O-])=C/C(C)=[O:15]>>[CH3:1][C:2]1([CH3:10])[CH2:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[C:7]1=[O:15]
Reactant: CC1=CC(C)(C)CC(=O)C1
Reactant: CC(=O)/C=C(/C)[O-]
Product: CC1=CC(=O)CC(C)(C)C1=O

Procedure:
A mixture of 1380 g of a product obtained according to the hereinabove given process (β-phorone content: 51.6%) and 7 g of cobaltIII -acetylacetonate (Wacker Chemie GmbH, Munich, West Germany) was heated to about 50° under vigorous stirring (turbine speed: 1000 t/min). Air was then added to the said mixture at an initial flow of about 100-150 l/h, this flow being then progressively increased to about 300 l/h.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
A mixture of 3-phenoxybenzoic acid (0.200 g, 0.934 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.215 g; 0.934 mmol), HATU (0.389 g; 1.03 mmol) and N,N-diisopropylethyldiamine (0.402 mL; 2.33 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified twice by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.068 g (19%) of the title compound as a colourless solid.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[C:36]([CH:35]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:39])[CH3:38]
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(C)=O)cc1O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.1 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-methoxy-5-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.60 mg, 22.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.52 (d, 2H, J=2.4 Hz), 7.3-7.2 (m, 5H), 7.20 (m, 3H), 6.97 (apparent d, 1H, J=6.7 Hz), 6.69 (apparent d, 1H, J=8.0 Hz), 5.47 (apparent dd, 1H, J=4.3, 7.8 Hz), 3.95 (s, 3H), 3.38 (m, 2H), 2.93 (m, 2H), 2.61 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.6 Hz), 2.50 (s, 3H), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 529.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:23][C:24](=[O:26])[CH3:25]>>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([CH2:23][C:24](=[O:26])[CH3:25])[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Reactant: CC(=O)CCl
Product: COC(=O)c1nn(CC(C)=O)c(C(=O)OC)c1OCc1ccccc1

Procedure:
The title compound was prepared from dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate using a procedure similar to that described in Example 2, Step 2, except that chloroacetone was used in place of bromo(phenyl)acetonitrile, and the silica gel chromatography gradient elution was 0-60% EtOAc/hexanes. 1H NMR (400 MHz, d6-DMSO) δ 7.46-7.34 (m, 5h), 5.44 (s, 2H), 5.06 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.20 (s, 3H); ES MS (M+1)=347.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[C:19](=[O:21])=[O:20]>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:19]([OH:21])=[O:20])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
A solution of 8.00 g (33.8 mmol, Aldrich) of 6-bromo-2-methoxynaphthalene in 75 ml of dry THF was cooled to -78° C. and 36 ml (1.8M in pentane, 65 mmol, Aldrich) of t-butyllithium was added over 30 minutes. The reaction mixture was stirred for 30 minutes at -78° C. then warmed to -20° C. for 30 minutes. The mixture was recooled to -78° C. and b 8.00 g (180 mmol) of crushed dry ice was added to the slurry, and then this was allowed to warm to room temperature over 2 hours. The mixture was concentrated in vacuo, 100 ml of 1N HCl was added to the residue and this was extracted with 100 ml of hot EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated in vacuo to give a solid. Purification via recrystallization (EtOAc/petroleum ether) afforded 5.80 g (85%) of the title compound as small white needles: m.p. 198°-200° C.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[CH:29]([NH:31][NH2:32])=[O:30]>C(Cl)(Cl)Cl>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([NH:32][NH:31][CH:29]=[O:30])[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Reactant: NNC=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(NNC=O)n2)cc1OC
Temperature: 25 °C
Yield: 26.4 %

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (3.0 g) in chloroform (15 ml) was added formylhydrazine (1.36 g). The mixture was refluxed for 6 hours and cooled to ambient temperature. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-(2-formylhydrazino)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.84 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10](N)=[N:9][N:8]=2)[CH:2]=1.C(O)(=O)C.[ClH:17].N([O-])=O.[Na+]>O.[Cu]>[Cl:17][C:10]1[S:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][N:9]=1
Reactant: Nc1nnc(-c2cccnc2)s1
Reactant: Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nnc(-c2cccnc2)s1
Temperature: 23 °C
Yield: 72 %

Procedure:
To a mixture of 5-pyridin-3-yl-[1,3,4]thiadiazol-2-ylamine (5.5 g, 30.9 mmol) and copper powder (0.335 g, 5.27 mmol), in a mixture of glacial acetic acid (93 mL) and concentrated hydrochloric acid (19 mL) at 0° C., was added dropwise a solution of sodium nitrite (10.67 g, 154.6 mmol) dissolved in water (13 mL). The reaction mixture was then allowed to warm to 23° C. overnight. The reaction mixture was diluted with 300 g of ice, resulting in an emulsion, and extracted with dichloromethane (3×200 mL). The emulsion was then passed through a medium porosity scintered glass funnel containing celite. The cake was stirred and washed well with chloroform. The filtrate was combined with the organic extracts. The organic phase was dried over MgSO4 and concentrated to dryness to give the title compound as a yellow solid (4.42 g, 72%): 1H NMR (300 MHz, CDCl3) δ 9.08 (br s, 1H), 8.78 (br s, 1H), 8.29 (dt, J=8, 2 Hz, 1H), 7.49 (dd, J=8, 5 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[C:17]([C:19]1[CH:20]=[C:21]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:22]=[CH:23][CH:24]=1)#[N:18]
Reactant: N#Cc1cccc(CO)c1
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Product: COC(=O)c1ccnc(-n2nccc2OCc2cccc(C#N)c2)c1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and (3-cyanophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H14N4O3, 335. Found, 335.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][C:25](=O)[NH:24][C:23]=4[CH:29]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.Cl>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][CH:25]=[N:24][C:23]=4[CH:29]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1COc2ccc(Nc3ncc(F)c(Nc4cccc([N+](=O)[O-])c4)n3)cc2N1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(Nc2nc(Nc3ccc4c(c3)N=CCO4)ncc2F)c1
Yield: 21.2 %

Procedure:
N4-(3-Nitrophenyl)-N2-[(2H)1,4-benzoxazin-3(4H)-one-6-yl]-5-fluoro-2,4-pyrimidinediamine (940 mg, 2.5 mmol) and Pd/C10% (300 mg, 50% water content) were suspended in EtOH (7 mL) and 10% aqueous HCl (5 mL) and hydrogenated in a Parr apparatus for 3 hours (22° C., 60 psi). The suspension was filtered over celite and neutralized by addition of K2CO3. The solvents were removed and the resulting black slurry was suspended in MeOH. Silica gel (4 g) was added and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give 186 mg of N4-(3-aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine as brownish solid. 1H NMR (DMSO-d6): δ 8.92 (s, 1H), 8.64 (s, 1H), 7.95 (d, 1H, J=3.6 Hz), 7.11 (s, 1H), 6.84-6.95 (m, 3H), 6.66 (dd, 1H, J=2.4, 9.0 Hz), 6.46 (d, 1H, J=8.1 Hz), 6.28 (d, 1H, J=8.1 Hz), 5.62 (s, 1H), 4.98 (s, 2H), 4.03 (m, 2H), 3.31 (m, 2H); LCMS purity: 98.4%; MS (m/e): 352.7 (M+, 100).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11](Cl)=[O:12])[CH3:2].[N+:14](=[CH2:16])=[N-:15]>C(Cl)Cl.CCOCC>[N+:14](=[CH:16][C:11](=[O:12])[CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])=[N-:15]
Reactant: C=[N+]=[N-]
Reactant: CCc1ccccc1CCC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1ccccc1CCC(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A solution of 3-(2-ethylphenyl)propanoyl chloride (crude, 23.8 mmole) in methylene chloride was slowly added to a solution of diazomethane (generated from 15.6 g of 1-methyl-3-nitro-1-nitrosoguanidine) in ether (100 ml) cooled in an ice bath. The mixture was then warmed up to room temperature and stirred overnight. The mixture was concentrated in vacuo and purified by column chromatography (10→20% ethyl acetate/hexanes) to give 1-diazo-4-(2-ethylphenyl)butan-2-one (3.47 g, 72% over 2 steps). 1H NMR (CDCl3) δ 7.1-7.25 (4H, m, phenyl), 5.21 (1H, broad s, diazo), 2.97 (2H, m, CH2 of ethyl), 1.20 (3H, t, CH3). Step 3:
Reaction SMILES: C(OC[N:10]1[C:15]2[CH:16]=[C:17]([N:20]3[C:24](=[O:25])[CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:34])C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].O1CCCC1>[O:25]=[C:24]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]3[O:13][CH2:12][C:11](=[O:34])[NH:10][C:15]=3[CH:16]=2)[CH2:21][C@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(=O)N(c2ccc3c(c2)N(COCc2ccccc2)C(=O)CO3)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Temperature: 100 °C
Yield: 92.6 %

Procedure:
To a mixture of tert-butyl [(3R)-1-{4-[(benzyloxy)methyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}-5-oxopyrrolidin-3-yl]carbamate (15.0 g, 32.1 mmol), ammonium formate (6.93 g, 110 mmol), methanol (250 ml) and tetrahydrofuran (93 ml) was added 10% Palladium on carbon (50% wet, 15.0 g) and the mixture was heated under reflux for 1 hour on an oil bath at 100° C. Ammonium formate (7.00 g, 111 mmol) was added and the mixture was further heated under reflux for 1 hour. Subsequently the catalyst was removed by filtration and the residue was washed thoroughly with a mixed solvent of chloroform-methanol (1:1). The filtrate and washings were combined to remove the solvent under reduced pressure and the residue was suspended in water from which the insoluble material was removed by filtration. The residue was washed with water and dried with heating under reduced pressure. 10.33 g (93%) of the title compound was obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][C:6](Cl)(Cl)[C:5]2=[O:19].C(O)(=O)C>C(O)C.[Pd]>[Cl:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][C:5]2=[O:19]
Reactant: N#Cc1c(Cl)c(-c2cccnc2)n2c1C(=O)C(Cl)(Cl)CC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1c(Cl)c(-c2cccnc2)n2c1C(=O)CCC2
Yield: 87.5 %

Procedure:
A suspension of 10.14 g of 2,7,7-trichloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 300 cm3 of acetic acid in 1000 cm3 of ethanol is stirred under argon, and 3.06 g of 10% palladium on carbon in 50 cm3 of ethanol are added. The reaction mixture is bubbled with hydrogen for 2 hours at room temperature, and then filtered on No. 3 sintered glass covered with Celite. The cake is washed with twice 50 cm3 of ethanol and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 55° C. An oily residue is taken up in 150 cm3 of water and the pH is brought to 8-9 by addition of sodium hydrogen carbonate. 7.08 g of 2-chloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile are obtained in the form of a white solid melting at a temperature greater than 260° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>>[C:31]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)Cl
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CCC(=O)N1CC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([N:6]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:31])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>N1C(C)=CC(C)=CC=1C>[CH:1]1([N:6]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11]([O:31][C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(Br)cc1)N(C1CCCC1)C1CCCC1
Reactant: COc1ccc(O)cc1OC
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Oc2ccc(C(=O)N(C3CCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N,N-dicyclopentyl amide (1.839 g, 5.47 mmol), 3,4-dimethoxy phenol (876 mg, 5.68 mmol) and cuprous oxide (413 mg, 2.89 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 179.95° C. (DSC).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5](=[C:6]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH2:4][CH2:3]1.[H][H]>C(O)(=O)C.C(O)C.[Pt]=O>[CH:11]1[C:12]2[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:6](=[C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:22][CH2:21]3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Yield: 94.2 %

Procedure:
Dissolved cyproheptadine (22.2 g, 0.077 mol) in 150 mL of glacial acetic acid and 20 mL of ethanol. Added platinum oxide catalyst (1.0 g), and hydrogenated on Paar shaker at 57 psi of hydrogen pressure for 5 hours. Filtered, and evaporated filtrate to give a solid. Recrystallized crude product from ether-pet ether to give 21.0 g (94% yield) of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine as a white solid.