Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:21]1([NH:27][CH2:28][CH2:29][NH:30][CH3:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(OCC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:30]([CH3:31])[CH2:29][CH2:28][NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCNc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCNc1ccccc1)CC2

Procedure:
Here, 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane (9 g, 0.0336 mol) is heated to 130° C. for 30 minutes with N-(2-phenylaminoethyl)-methylamine (11 g, 0.073 mol). After cooling, the reaction mixture is distributed between water and diethylether. The organic phase is separated, dried over sodium sulfate and concentrated by evaporation. The residue is recrystallized from toluene/petroleum ether.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[N:30]1([C:35]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:3]([CH3:29])=[C:2]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([N:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[CH:36]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: OB(O)c1cccc(N2CCCC2)c1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N3CCCC3)c1)OCC2c1ccc(C(C)C)cc1
Yield: 17 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-(1-pyrrolidinyl)phenyl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 17%. Melting point: 206-207° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:20][CH2:19][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[OH-].[Na+]>O1CCCC1.Cl>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:20][CH2:19][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: CCOC(=O)c1ccc2oc3c(c2c1)CC(N(C)C)CC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C1CCc2oc3ccc(C(=O)O)cc3c2C1
Temperature: 35 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
A mixture of 0.21 gm (0.73 mMol) N,N-dimethyl-8-ethoxycarbonyl-1,2,3,4-tetrahydro-2-dibenzofuranamine and 25 mL 2N sodium hydroxide in 25 ml tetrahydrofuran was stirred at 35° C. for 18 hours. The reaction mixture was cooled to room temperature and washed with dichlorometh-ane. The aqueous phase was adjusted to pH~7, saturated with sodium chloride, and then extracted well with chloroform containing 10% isopropanol. Organic extracts were combined and concentrated under reduced pressure to provide a white solid which was taken up in hydrochloric acid. The colorless crystalline precipitate which formed was filtered and dried to provide 0.098 ggm (55%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][C:14]([Cl:24])=[CH:13][CH:12]=2.[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:40]2[C@@H:39]([NH2:43])[CH2:38][CH2:37][CH2:36][C:35]=2[N:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:40]2[C@H:39]([NH:43][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]3[C:11]4[C:16]([N:17]=[C:18]5[C:23]=3[CH2:22][CH2:21][CH2:20][CH2:19]5)=[CH:15][C:14]([Cl:24])=[CH:13][CH:12]=4)[CH2:38][CH2:37][CH2:36][C:35]=2[N:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Clc1ccc2c(NCCCCCCCBr)c3c(nc2c1)CCCC3
Reactant: N[C@H]1CCCc2nc(OCc3ccccc3)ccc21
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2c(NCCCCCCCN[C@@H]3CCCc4nc(OCc5ccccc5)ccc43)c3c(nc2c1)CCCC3
Temperature: 25 °C
Yield: 32.3 %

Procedure:
A solution of (7-bromo-heptyl)-(6-chloro-1,2,3,4-tetrahydro-acridin-9-yl)-amine (180 mg, 0.43 mmoL) and (S)-2-benzyloxy-5,6,7,8-tetrahydro-quinolin-5-ylamine (108 mg, 0.43 mmoL) in dried N,N-dimethylformamide (2.1 ml) was heated up to 120 degree Celsius under nitrogen for 5 h. After cooling to room temperature, the reaction mixture was poured into icy water. The mixture was extracted with ethyl acetate. The combined ethyl acetate was dried, filtered and concentrated. The resulting crude product was purified by column chromatography on silica gel using hexane/ethyl acetate/triethyl amine (8/2/1) to give the desired product (80 mg, 0.14 mmoL) in 33% yield.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:9](=[O:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(O)(=O)C.Cl.[Pt]=O>[C:1]1([N:7]2[CH:11]=[C:10]([CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:9](=[O:18])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]n(-c2ccccc2)cc1-c1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]n(-c2ccccc2)cc1C1CCNCC1

Procedure:
Platinum oxide (60 mg) was added to a solution of 1-phenyl-4-pyridin-4-yl-1,2-dihydro-3H-pyrazol-3-one (180 mg, 0.758 mmol) in acetic acid (12 mL), concentrated hydrochloric acid (0.100 mL), and water (5 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (50 psi). After 5 h the mixture was filtered and concentrated to give the title compound. MS 244.3 (M+1).
Reaction SMILES: [N+](=[C:3]([C:7]([CH3:9])=[CH2:8])[C:4](=[O:6])[CH3:5])=[N-].[C:10]([O:14][C:15]([N:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CCCCCC.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[C:4]([C:3]1[CH:21]2[N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH:18]([CH2:8][C:7]=1[CH3:9])[CH:19]=[CH:20]2)(=[O:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)n1cccc1
Reactant: C=C(C)C(=[N+]=[N-])C(C)=O
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: CCCCCC
Product: CC(=O)C1=C(C)CC2C=CC1N2C(=O)OC(C)(C)C

Procedure:
A solution of 3-diazo-4-methylpent-4-ene-2-one (2.30 g, 18.5 mmol) in hexane (25 ml) was added over 3 hours by means of a syringe pump to a stirred solution of N-tert-butoxycarbonyl pyrrole (9.18 g, 55 mmol) and rhodium(II) octanoate (0.07 g, 0.09 mmol) in refluxing hexane (10 ml) under an argon atmosphere. The mixture was refluxed for a further 1 hour period, and solvent was then removed using a rotary evaporator under reduced pressure. Purification of the product by silica gel column chromatography (using 2 parts diethyl ether and 8 parts petroleum ether, and 4 parts diethyl ether and 6 parts petroleum ether) yielded 2-acetyl-3-methyl-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octa-2,6-diene, which is an orange liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([C@H:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)O)[CH2:4][O:3]1.CC1(C)O[C@@H]([C@@H](C2SC=CC=2)O)CO1.[C-]#[C-].[Na+].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45]1.N1C(C)=CC=CC=1C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([C@H:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=[CH:45]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H]([C@@H](O)c2cccs2)O1
Reactant: c1ccc2c(c1)CCN2
Agent: CC1(C)OC[C@H]([C@H](O)c2cccs2)O1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC1(C)OC[C@H]([C@H](c2cccs2)n2ccc3ccccc32)O1
Reaction time: 2 h

Procedure:
A mixture of (R)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol and (S)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol (1.5 g, 7.0 mmol) was dissolved in tetrahydrofuran (28 mL) and sodium acetylide (2.1 g, 7.7 mmol; 18 wt % slurry in xylenes/light mineral oil) and the mixture was stirred for 2 hours. para-Toluenesulfonyl chloride (1.46 g, 7.7 mmol) was added, and stirring was continued for 2 hours, then indoline (2.5 g, 21 mmol) was added followed by 2,6-lutidine (0.81 mL, 7.0 mmol). After 72 hours the mixture was quenched with a saturated aqueous solution of ammonium chloride, diluted with ethyl acetate, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 1-10% ethyl acetate in hexane) to afford 590 mg that was immediately dissolved in dioxane (10 mL) and treated with dichlorodicyanobenzoquinone (552 mg, 2.4 mmol) and stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 1-20% ethyl acetate in hexane) to afford 160 mg of 1-[(R)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methyl]-1H-indole. HRMS: calcd for C18H19NO2S+H+, 314.12092; found (ESI-FTMS, [M+H]1+), 314.12089.
Reaction SMILES: [C:1](=O)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2]CC1C=CC=CC=1.O.[NH2:20][NH2:21]>>[C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:2])[NH:20][NH2:21]
Reactant: NN
Reactant: O=C(OCc1ccccc1)OCc1ccccc1
Solvent: O
Product: NNC(=O)OCc1ccccc1

Procedure:
The 2nd step is carried out analogously in further experiments B, C, and D at room temperature using the dibenzyl carbonate and hydrazine hydrate ratios given in Table 1. The amount and purity of benzyl carbazate that is obtained are likewise summarized in Table 1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[CH3:8].Cl[CH2:18][C:19]#[N:20].N>C(O)C.O.CC(C)=O>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:18][C:19]#[N:20])[CH3:8]
Reactant: CCOc1ccccc1O
Reactant: N#CCCl
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: CCOc1ccccc1OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
Potassium carbonate (550 g, 3.98 mol) was added to acetone (1800 ml) and resulting suspension was stirred for 30 min. 2-Ethoxyphenol (460 g, 3.329 mol) was gradually added under stirring. The mixture was heated to reflux. Chloroacetonitrile (275 g, 3.642 mol) was added and the mixture was stirred under reflux for 24 hours. The reaction mixture was cooled down to room temperature. Solid was filtered off, washed with acetone (750 ml) and combined filtrates were evaporated to give oil. The oil was dissolved in ethanol (180 ml), the solution was heated to reflux and mixture of water (530 ml) and aqueous ammonia (45 ml) was added. The mixture was cooled to 5-10° C. under stirring. Crude crystalline product was filtered, washed with mixture of ethanol (250 ml) and water (400 ml). The crude product was recrystallized from ethanol /water mixture to give pure product (500 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:9]=[CH:10][C:4]=2[C:3]=1O.[H-].[Na+].FC(F)(F)S(N(C1C=CC=CC=1)S(C(F)(F)F)(=O)=O)(=O)=O.[N:44]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[C:3]([N:47]2[CH2:46][CH2:45][N:44]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(Cn2ncc3c(O)c(Br)cnc32)cc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
A solution of 5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (10.85 g, 32.5 mmol) in DMF (130 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 1.56 g, 39 mmol) in DMF (70 mL) at room temperature. Once the addition was complete, the mixture was stirred at 40° C. for 30 minutes. The resulting solution was cooled to room temperature and treated with 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (13.92 g, 38.96 mmol). After 1 hour, solid tert-butyl piperazine-1-carboxylate (13.3 g, 71.43 mmol) was added in 2 portions with stirring, and the mixture was stirred at 80° C. for 1.5 hours. The resulting mixture was allowed to cool to room temperature overnight. Saturated NH4Cl solution (100 mL), water (50 mL) and EtOAc (250 mL) were then added to the reaction mixture. The phases were separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with water (1×50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was crystallized from boiling EtOAc (˜30 mL) and hexane (˜10 mL). The solid formed was filtered, washed with additional hexane (2×10 mL), and dried to provide tert-butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (14.8 g, 91% yield) as a solid. LCMS (APCI+) m/z 504 (M+H)+, Retention time=4.56 minutes.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[CH:17]([NH2:21])([CH2:19][CH3:20])[CH3:18].Cl>C(O)C>[CH:17]([NH:21][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4])([CH2:19][CH3:20])[CH3:18]
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CCC(C)N
Agent: Cl
Solvent: CCO
Product: CCC(C)NCC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Yield: 58.4 %

Procedure:
4.3 g of the 5-chloroacetyl-8-hydroxycarbostyril (IV) obtained in Example 4 or 8 was suspended in 50 ml of ethanol, and 5 g of sec-butylamine was added dropwise to the resulting suspension while stirring followed by stirring at 60° to 65° C. for 5 hours. After cooling, the resulting mixture was adjusted to a pH of 3 with concentrated hydrochloric acid. The precipitated crystals were filtered, washed with acetone and recrystallized from methanol-ethanol (1:1 by volume) to obtain 2.9 g of 5-sec-butylaminoacetyl-8-hydroxycarbostyril (II) hydrochloride having a melting point of 289° - 291° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(Cc2ccc(F)cc2)cn1
Yield: 70 %

Procedure:
As described for Example 34, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 4-fluorobenzyl bromide instead of benzyl bromide was converted to the title compound (104 mg, 70%) as a colourless gum. MS: m/e=334.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH2:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH2:16][CH3:17]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][CH:14]=1)[C:8](=[O:10])[N:22]([C:21]1[CH:23]=[CH:24][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)[C:11]2=[O:12])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCCc1ccc(N)cc1
Solvent: CC(=O)O
Product: CCCc1ccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Temperature: 25 °C

Procedure:
A solution of 95% 4-nitrophthalic acid anhydride (4.22 g, 20.7 mmol) and 4-propylaniline (2.81 g, 20.7 mmol) in acetic acid (86 ml) was refluxed by heating for 24 hours. The reaction solution was cooled to room temperature, and then added to ice water, and the deposited crystals were collected by filtration, and washed with water. The resulting crystals were purified by recrystallization (ethanol) to obtain 5-nitro-2-(4-propyl-phenyl)-isoindole-1,3-dione as pale yellow scaly crystals (5.89 g, yield: 91.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]=[C:6]1[CH2:9][S:8][CH2:7]1)[CH3:2].[C:11]1([CH2:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:17]([NH:18][C:6]1([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH2:9][S:8][CH2:7]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C=C1CSC1
Product: CCOC(=O)CC1(NCc2ccccc2)CSC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.3 %

Procedure:
A mixture of Thietan-3-ylidene-acetic acid ethylester (CAN 1223573-30-5, 1.8 g, 11.4 mmol) and phenylmethanamine (CAN 100-46-9, 1.22 g, 1.24 ml, 11.4 mmol) was stirred for 14 hours at ambient temperature. The crude product was directly purified without any work-up protocol. The crude material was purified by flash chromatography on silica eluting with a heptane-ethyl acetate gradient to yield the title compound (2.4 g, 80%). MS (ESI, m/z): 266.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[OH:21])[C:7]=2[C:6]=1[CH3:23])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:31]1[CH2:34][CH2:33][CH2:32]1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:7]=2[C:6]=1[CH3:23])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC3)c2c1C
Temperature: 60 °C

Procedure:
A mixture of 4-(4-fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (200 mg), potassium carbonate (166 mg) and bromocyclobutane (113 μl) in DMF (3 ml) was stirred at 60° C. over the weekend. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was concentrated and the residue was triturated with diethyl ether to give the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[C:5]([F:12])=[C:4]([CH3:13])[N:3]=1.[S:14]1[C:18]([C@:19]23[CH2:27][NH:26][CH2:25][C@H:24]2[CH2:23][S:22][C:21]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:20]3)=[CH:17][CH:16]=[N:15]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:12][C:5]1[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:7][C:2]([N:26]2[CH2:25][C@@H:24]3[C@@:19]([C:18]4[S:14][N:15]=[CH:16][CH:17]=4)([N:20]=[C:21]([NH:28][C:29](=[O:36])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[S:22][CH2:23]3)[CH2:27]2)=[N:3][C:4]=1[CH3:13]
Reactant: O=C(NC1=N[C@@]2(c3ccns3)CNC[C@H]2CS1)c1ccccc1
Reactant: Cc1nc(Cl)nc(C(C)(C)O)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccns3)C2)nc(C(C)(C)O)c1F
Temperature: 110 °C
Reaction time: 0.05 h
Yield: 17.8 %

Procedure:
2-(2-Chloro-5-fluoro-6-methyl-pyrimidin-4-yl)propan-2-ol (104 mg, 0.51 mmol) is dissolved in 1,4-dioxane (3 mL). N-[(4aR,7aR)-7a-Isothiazol-5-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (125 mg, 0.36 mmol) is added followed by diisopropylethylamine (158 μL, 0.91 mmol). The reaction is heated via microwave irradiation in a sealed microwave vessel to 110° C. for 1 hr. The reaction is concentrated to give the crude product. The crude product is purified via HPLC using a Waters XBridge 5 μm C18 OBD 30×75 mm column and eluted with a gradient of: 36% β isocratic for 3 min followed by 36-51% B over 5 min where solvent A is 10 mM ammonium bicarbonate in water with 5% MeOH and solvent B is acetonitrile. The desired fractions are combined and diluted with saturated NaHCO3 (aq, 100 mL). The mixture is extracted with 4:1 CHCl3: isopropanol (3×100 mL). The organic layers are combined, washed with brine (1×50 mL), dried over MgSO4, filtered and concentrated to give the title compound (33 mg, 0.064 mmol): EZ/MS (m/z): 513 (M+H).
Reaction SMILES: O[N:2]=[C:3]1[CH2:6][CH:5]([NH:7][C:8](=NO)[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:4]1([CH3:17])[CH3:16].C[OH:19]>N.[Ni]>[NH2:2][CH:3]1[CH2:6][CH:5]([NH:7][C:8](=[O:19])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:4]1([CH3:17])[CH3:16]
Reactant: CO
Reactant: CC(C)(C)OC(=NO)NC1CC(=NO)C1(C)C
Agent: [Ni]
Agent: N
Product: CC(C)(C)OC(=O)NC1CC(N)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of tert-butyl (3-(hydroxyimino)-2,2-dimethylcyclobutyl)carbamate oxime (730 mg, crude) in MeOH and ammonia (12.5 mL and 2.5 mL) was added Raney-Ni (430 mg, crude). The reaction mixture was stirred at room temperature under hydrogen atmosphere overnight. The reaction was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (2-5% MeOH in DCM) to afford the title compound (490 mg, 2.29 mmol, 76% yield two steps). MS (ESI) m/z 215.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1)([O-])=O.O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CCN(c2ccncc2N)CC1
Yield: 95.1 %

Procedure:
A mechanically stirred solution of ethyl 4-(3-nitro-4-pyridinyl)-1-piperazinecarboxylate (10 g, 35.7 mmol) and iron filings [40 mesh](21.7 g, 389 mmol) in a mixture of 50 mL of ethanol, 7 mL of water and 0.36 mL of concentrated HCl was heated to reflux for 4 h. The hot solution was filtered and concentrated in vacuo to give of ethyl 4-(3-amino-4-pyridinyl)-1-piperazinecarboxylate (8.5 g, 95%). An analytical sample was obtained by recrystallization from ethyl acetate in hexanes: mp 141°-142° C. Anal. Calcd for C12H18N4O2 : C, 57.58; H, 7.25; N, 22.38. Found: C, 57.43; H, 7.19; N, 22.24.
Reaction SMILES: C([O:8][CH2:9][C:10]1[C:11]([O:28][CH3:29])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:27])([CH2:25][CH3:26])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C1C=CC=CC=1>[Pd].C(O)C>[OH:27][C:16]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:28][CH3:29])[C:10]=1[CH2:9][OH:8])([CH2:25][CH3:26])[CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19]
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1CO
Yield: 89.9 %

Procedure:
tert-Butyl 3-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-3-hydroxypentanoate (1 g, 2.5 mmol) is subjected to hydrogenolysis at atmospheric pressure and at ambient temperature using 5% palladium on carbon as catalyst (50 mg) and absolute ethanol as solvent (10 ml). Once the reaction has terminated (6 hours), the catalyst is separated by filtration and the solvent is evaporated off, which leaves 0.7 g (90%) of product (K) of a sufficient purity for a subsequent synthetic use.