Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]([NH2:32])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].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=O)C.O.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]([NH:32][C:7]([C:6]2[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[S:3][C:2]=2[NH2:1])=[O:9])[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc(-c2cc(C(=O)O)c(N)s2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H](N)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C(=O)N[C@H]3CCCCN(C(=O)OC(C)(C)C)C3)c(N)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a stirred solution of 2-amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid (1.0 g, 4.0 mmol) in anhydrous DMF (20 mL) is added (S)-3-amino-azepane-1-carboxylic acid tert-butyl ester (1.03 g, 4.8 mmol), BOP (2.6 g, 6.0 mmol) and NMM (0.6 mL, 5 mmol). The reaction mixture was stirred overnight at room temperature. The solution was diluted with water and EtOAc. The organic layer was separated and set aside. The remaining aqueous layer was extracted with EtOAc (2×) and then the combined organic extracts were pooled and washed with brine. The resultant EtOAc solution was dried over Na2SO4, filtered, and concentrated under vacuum to yield a brown solid. Purification was performed by ISCO MPLC (SiO2, 30-50% EtOAc/hexanes) to give 0.9 g (50%) of an off-white solid. 1H NMR (d6-DMSO δ 7.51, d, 0.5H; δ 7.46, s, 0.5H; δ 7.37, s, 0.5H; δ 7.36, d, 0.5H; δ 7.34, br s, 2H; δ 7.33, d, 2H; δ 6.93, d, 2H; δ 4.11, br s, 1H; δ 3.76, s, 3H; δ 3.61, dq, 1H; δ 3.47, m, 1H; δ 3.11, m, 2H; δ 1.73, m, 3H; δ 1.56, m, 2H; δ 1.42, s, 4.5H; δ 1.38, s+m, 5.5H;), LC/MS (APCI, ES, M+H=446).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]([C:16]([O:18][CH2:19][C:20](=[O:40])[C:21]2[CH:22]=[CH:23][C:24]3[C:33]4[CH:32]=[C:31]5[CH2:34][CH2:35][CH2:36][C:37](=[O:38])[C:30]5=[CH:29][C:28]=4[O:27][CH2:26][C:25]=3[CH:39]=2)=[O:17])[CH2:5]1.[Br-:41].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[C@H:6]([C:16]([O:18][CH2:19][C:20]([C:21]2[CH:22]=[CH:23][C:24]3[C:33]4[CH:32]=[C:31]5[CH2:34][CH2:35][CH:36]([Br:41])[C:37](=[O:38])[C:30]5=[CH:29][C:28]=4[O:27][CH2:26][C:25]=3[CH:39]=2)=[O:40])=[O:17])[CH2:5]1
Reactant: [Br-]
Reactant: COC[C@H]1CC(C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
(4S)-1-tert-Butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.66 g, 13.9 mmol) was dissolved in a solution of DCM (100 mL) and MeOH (40 mL), then treated with pyridinium tribromide (4.90 g, 15.3 mmol). After stirring at RT for 1.75 h, the reaction mixture was diluted with DCM and washed successively with 10% HCl, saturated aqueous NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([OH:12])[CH:4]=1.Cl[CH2:14][CH2:15][OH:16]>CN(C=O)C>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([O:12][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: OCCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCO)cc1
Temperature: 100 °C
Yield: 92 %

Procedure:
Sodium hydroxide (6.22 g) is added to a solution of p-nitrophenol (21.45 g) in DMF (300 mL) and stirred until the reagents are fully dissolved. After a dropwise addition of 2-chloroethanol (10.66 ml), the reaction mixture is heated to 100° C. for 72 hours. After filtering and evaporating the solvent under reduced pressure, the resulting oil is recrystallized in a methanol/water mixture and filtered to afford 21.62 g (92%) of 2-(4-nitrophenoxy)-1-ethanol. A mixture of 2-(4-nitrophenoxy)-1-ethanol (6.17 g) and palladium on carbon (0.08 g) in EtOH (120 mL) is hydrogenated in a 500 mL Parr jar at 33 psi for 18 hrs. Vacuum filtration through celite and evaporation under reduced pressure affords 5.00 g (96%) of 2-(4-aminophenoxy)-1-ethanol. This material is combined with diethyl ethoxymethylenemalonate (7 mL) and heated to 130° C. for 1 hr in a round bottom flask under a gentle stream of nitrogen. The mixture is cooled, diluted with 1:1 cyclohexane/toluene (20 mL), and filtered to afford 9.1 g (86%) of diethyl 2-{[4-(2-hydroxyethoxy)anilinorlmethylene}-malonate. A solution the resulting malonate (8.59 g) in acetic acid (15 mL) and acetic anhydride (4 mL) is heated to 60° C. for 36 hrs. The reaction mixture is diluted with water, extracted with ethyl acetate and washed with saturated sodium bicarbonate. Evaporation under reduced pressure leaves a brown oil which is recrystallized from 1:1 methanol/water and filtered to afford 7.09 g (73%) diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate. Diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate (6.55 g) is dissolved in diphenyl ether (75 mL) and refluxed at 250° C. for 1 hr. After the mixture is cooled and diluted with 250 mL toluene, the resulting precipitate is collected by filtration, washed with toluene and recrystallized from aqueous acetic acid. This procedure yielded 0.50 g (9%) of ethyl 6-[2-(acetyloxy)ethoxy]-4-hydroxy-3-quinolinecarboxylate. The resulting carboxylate ester (0.49 g) and 4-chlorobenzylamine (0.90 mL) are heated to 175° C. for 2 hrs. After the reaction mixture is cooled and diluted with xylenes, the dark solid is filtered. Recrystallization from acetic acid and water affords 0.150 g (26%) of the title compound as a beige solid.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:33])(=O)C.[CH3:34][CH:35]1[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1>>[CH3:34][CH:35]1[CH2:36][CH2:37][C:38](=[O:40])[N:39]1[C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:9]([N:6]2[CH2:7][CH2:8][NH:4][C:5]2=[O:33])[CH:14]=1
Reactant: CC1CCC(=O)N1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)C1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3N3CCNC3=O)CC2)nc1C
Yield: 18.9 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (182 mg) described in Preparation Example 258 and 5-methylpyrrolidin-2-one (58 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (36 mg) was obtained.
Reaction SMILES: [CH2:1]([C:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[NH:22][C:21]([C:23]([C:55]4[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=4)=[C:24]4[N:54]=[C:27]([C:28]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[C:29]5[NH:46][C:32](=[C:33]([C:39]6[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=6)[C:34]6[CH:35]=[CH:36][C:37]=2[N:38]=6)[CH:31]=[CH:30]5)[CH:26]=[CH:25]4)=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[Zn:62](OC(C)=O)OC(C)=O.O.O>C(Cl)(Cl)Cl.CO>[Zn+2:62].[CH2:1]([C:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]3[NH:22][C:21]([C:23]([C:55]4[CH:56]=[CH:57][C:58]([CH3:61])=[CH:59][CH:60]=4)=[C:24]4[N:54]=[C:27]([C:28]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[C:29]5[NH:46][C:32](=[C:33]([C:39]6[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=6)[C:34]6[CH:35]=[CH:36][C:37]=2[N:38]=6)[CH:31]=[CH:30]5)[CH:26]=[CH:25]4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=1)([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: CC(=O)O[Zn]OC(C)=O
Agent: C=CCC(CC=C)(CC=C)c1ccc(-c2c3nc(c(-c4ccc(C)cc4)c4ccc([nH]4)c(-c4ccc(C)cc4)c4nc(c(-c5ccc(C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: [Zn+2]
Reaction time: 2 h

Procedure:
A solution of 1 (132 mg, 167 μmol) in CHCl3 (13 mL) was treated with a solution of Zn(OAc)2.2H2O (183 mg, 0.832 mmol) in MeOH (2.6 mL) at room temperature. The reaction was followed by TLC. The reaction was complete in 2 h. The reaction mixture was washed with saturated aqueous NH4Cl and extracted with CH2Cl2. The combined organic layer was dried (Na2SO4), concentrated and chromatographed [silica, hexanes/ethyl acetate (9:1)] to afford a pink solid (132 mg, 93%): 1H NMR δ 2.66-2.78 (m, 15H), 5.12-5.28 (m, 6H), 5.80-5.96 (m, 3H), 7.50-7.60 (m, 6H), 7.67 (d, J=8.4 Hz, 2H), 8.04-8.14 (m, 6H), 8.16 (d, J=8.4 Hz, 2H), 8.88-8.94 (m, 2H), 8.94-9.02 (m, 6H); MALDI-MS obsd 852.4; FABMS obsd 852.3193, calcd 852.3170 (C57H48N4Zn); λabs 424, 551 nm.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:27]=[C:28]=[S:29])(=O)C1C=CC=CC=1>>[C:1]1([N:7]2[C:11]([NH:12][C:28]([NH2:27])=[S:29])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccc1
Product: NC(=S)Nc1cc(-c2ccccc2)nn1-c1ccccc1

Procedure:
1,3-Diphenyl-5-amino pyrazole (117.5 g.) and benzoyl isothiocyanate (89.65 g.) were reacted as described in Example IV to give 119.8 g. of product, mp 198°-201° C.
Reaction SMILES: S(Cl)(Cl)=O.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[S:10][CH2:11][CH:12]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([OH:15])=O.Cl[Sn](Cl)(Cl)Cl.O>CN(C=O)C.C(Cl)Cl>[O:15]=[C:13]1[CH:12]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][S:10][C:6]2[S:5][CH:9]=[CH:8][C:7]1=2
Reactant: CCOC(=O)CCC(CSc1cccs1)C(=O)O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)CCC1CSc2sccc2C1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 97.1 %

Procedure:
Under N2, thionyl chloride (5.5 g, 0.043 mol) was added dropwise to a solution of 1 (11.5 g, 0.04 mol) in DMF (4 drops) and methylene chloride (100 ml). After the addition, the solution was stirred at room temperature for 4.5 hours. The mixture was then cooled to -10° and SnCl4 (5.3 g, 0.02 mol) was added dropwise. After the addition the reaction was allowed to stir at room temperature for 28 hours. The mixture was then added to H2O and the aqueous layer extracted with EtOAc (3×). The organic extracts were backwashed with saturated NaHCO3, dried, filtered and concentrated to dryness to yield 10.5 g (97%) of 2 wherein R1, R2, R3 and R4 are each H.
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[C:39]#[N:40])[CH2:30][CH2:29]1>CCOC(C)=O>[C:39]([C:38]1[CH:37]=[C:36]([CH2:35][CH2:34][CH:31]2[CH2:32][CH2:33][N:28]([C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=3)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:29][CH2:30]2)[CH:43]=[CH:42][CH:41]=1)#[N:40]
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: N#Cc1cccc(CCC2CCNCC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C#N)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (723 mg) was added to an acetonitrile (10 ml) solution of 3-[2-(4-piperidyl)ethyl]benzonitrile hydrochloride (475 mg) and TEA (0.58 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, followed by washing with an aqueous saturated sodium hydrogencarbonate solution and drying over anhydrous magnesium sulfate. The solvent was evaporated, the resulting residue was subjected to basic silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) and the side-product, nitrophenol was removed. Then, this was purified by silica gel column chromatography (eluent: hexane:EtOAc=3:2 (v/v)) to obtain methyl 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (284 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].FC1C=CC(C[N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=CC=1.C(O)(=O)C>CO>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:1][CH2:2][N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:18]2[NH:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)[CH2:32][CH2:31]1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: C=Cc1cnccn1
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2[nH]c(NC3CCN(CCc4cnccn4)CC3)nc2c1

Procedure:
A mixture of 1.27 parts of 2ethenylpyrazine, 6.48 parts of 1-[(4 fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 0.3 parts of acetic acid and 40 parts of methanol was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (88:12 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was washed with 2,2'-oxybispropane and crystallized from 27 parts of methylbenzene, yielding 2.4 parts of 1-)4-fluorophenylmethyl)-N-[1-[2-(2-pyrazinyl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 165.3° C. (compound 101).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[C:5]([CH3:10])[CH:4]=1.Cl[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[F-].[Cs+].[OH-].[Na+]>CC#N>[CH3:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[S:9][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCl
Reactant: COc1ccc(S)c(C)c1
Agent: [Cs+]
Agent: [F-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(SCCC(=O)O)c(C)c1

Procedure:
A mixture of 16.1 g 4-methoxy-2-methylbenzenethiol, 20 g 3-chloropropionic acid and 31.5 g CsF in 200 ml CH3CN is refluxed 40 hours. The cooled reaction mixture is poured into 200 ml 1N NaOH, and washed with 500 ml ether. The aqueous phase is acidified with 12N HCl and extracted with three 100 ml portions of CH2Cl2. The combined extracts are washed to 100 ml brine, dried over Na2SO4, filtered and evaporated to dryness in vacuo to afford 3-[(2-methyl-4-methoxyphenyl)thio]propanoic acid.
Reaction SMILES: [CH2:1]([C:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[N:7]2[N:6]=[C:5]1[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:39].[Na+].OO>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH2:9][CH:8]3[C:4]([CH2:1][CH2:2][CH2:3][OH:39])([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:5]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:6][N:7]3[C:12]=2[CH:13]=1
Reactant: C=CCC1(c2ccccc2)C(C(=O)N(C)OC)=NN2c3cc(Cl)ccc3OCC21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCCO)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Allyl-8-chloro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-2; a racemic mixture, 0.26 g, 0.64 mmol) was dissolved in anhydrous THF (5 mL) and treated with a 0.5M solution of 9-BBN (5.1 mL, 2.6 mmol) and stirred at 50° C. for 2 h. The reaction was cooled to 0° C. and treated with 3N NaOH (1 mL) and 30% H2O2 in water (1 mL), and stirred an additional hour. Upon completion, the reaction was quenched with the addition of brine (5 mL), and extracted with EtOAc (3×10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude residue was subjected to flash column chromatography (ISCO Redisep 40 g SiO2 column, 0-100% EtOAc/hexanes gradient) to provide pure 8-chloro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-3; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=2.1 Hz 1H), 7.43-7.24 (m, 5H), 6.83 (d, J=8.5, 2.1 Hz, H), 6.77 (d, J=12.5 Hz, 1H), 3.99 (dd, J=10.5, 3.5 Hz, 1H), 3.91 (s, 3H), 3.76 (br s, 1H), 3.56 (dd, J=11.0, 3.7 Hz, 1H), 3.32 (s, 3H), 2.93 (t, J=10.7 Hz, 1H), 2.59 (dt, J=12.2, 4.9 Hz, 1H), 2.42 (dt, J=12.2, 4.6 Hz, 1H), 1.90-1.60 (m, 4H); MS (M+H+, C22H24ClN3O4) 430.4 found 430.9 required.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([CH:23]=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1.[N:27]1([CH2:33][CH2:34][OH:35])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.C(OCC)C>ClCCCl.C(Cl)Cl.CO.C(O)(=O)C>[F:26][C:2]([F:1])([F:25])[CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([C:16]4[CH:19]=[C:20]([CH2:23][N:30]5[CH2:31][CH2:32][N:27]([CH2:33][CH2:34][OH:35])[CH2:28][CH2:29]5)[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12]3)[N:18]=2)=[N:7][CH:6]=[N:5]1
Reactant: OCCN1CCNCC1
Reactant: O=Cc1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: OCCN1CCN(Cc2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehyde (175 mg, 0.48 mmol) and piperazine ethanol in DCE (15 mL) was treated with sodium triacetoxyborohydride (153 mg, 0.72 mmol) and catalytic acetic acid and then stirred at RT for 72 h. The resultant mixture was diluted with DCM and washed with saturated aqueous sodium hydrogen carbonate then dried (Na2SO4), filtered and concentrated in vacuo to give a colourless gum which was subjected to flash chromatography (SiO2, gradient 0-10% MeOH in DCM). The appropriate fractions were combined, concentrated in vacuo and the resultant residue dissolved in diethyl ether and treated with 1M HCl in diethyl ether (2 mL, 2 mmol). The resultant precipitate was filtered off, washed with ether and dried in vacuo to give 128 as a white solid. 1H NMR (DMSO-d6 plus deuterated TFA, 400 MHz): δ 8.22 (s, 1H); 8.16-8.12 (m, 1H); 7.66-7.60 (m, 1H); 7.39 (d, J=8.3 Hz, 1H); 7.02 (s, 1H); 5.75 (q, J=8.7 Hz, 2H); 4.57 (t, J=5.9 Hz, 2H); 4.52 (s, 2H); 3.76 (t, J=5.0 Hz, 2H); 3.61 (br s, 8H); 3.32 (s, 2H); 3.24 (t, J=5.9 Hz, 2 H). 1 Exchangeable not observed. LCMS: RT=6.56 min, M+H+=478
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([S:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-nitroaniline (4-7) (13.8 g, 100 mmol) and phenylsulfonyl chloride (14 mL, 100 mmol) in pyridine (50 mL) was heated at 100° C. for 2 h. The resultant solution was concentrated, and the residue dissolved in ethyl acetate. The organic extract was washed successively with 2M hydrochloric acid, sat. aq. sodium bicarbonate brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was dissolved in a minimum amount of ethyl acetate with warning, and hexane added until the solution turned cloudy. The mixture was allowed to cool slowly to RT and then chilled at 0° C. The yellow solid precipitated was obtained by filtration. Further drying under vacuum overnight provide N-phenylsulfonyl-4-nitroaniline.
Reaction SMILES: C(O/[N:5]=[C:6](/[C:8]1[CH:9]=[C:10]([C:15]2([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[OH:14])\[CH3:7])(=O)C.N1C=CC=CC=1.O>CN(C=O)C>[CH3:7][C:6]1[C:8]2[CH:9]=[C:10]([C:15]3([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]3)[CH:11]=[CH:12][C:13]=2[O:14][N:5]=1
Reactant: COC(=O)C1(c2ccc(O)c(/C(C)=N/OC(C)=O)c2)CC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C1(c2ccc3onc(C)c3c2)CC1
Yield: 81.9 %

Procedure:
A solution of (E)-methyl 1-(3-(1-(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropane carboxylate (10.5 g, 39.6 mmol) and pyridine (31.3 g, 396 mmol) in DMF (150 mL) was heated at 125° C. for 10 h. The cooled reaction mixture was poured into water (250 mL) and was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give methyl 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylate (7.5 g, 82%). 1H NMR (CDCl3 300 MHz) δ 7.58-7.54 (m, 2H), 7.48 (dd, J=1.5, 8.1 Hz, 1H), 3.63 (s, 3H), 2.58 (s, 3H), 1.71-1.68 (m, 2H), 1.27-1.23 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=2)[N:13]=[CH:12][N:11]=1.C(NC(C)C)(C)C>C1COCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[Cl:9])=[O:4]
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: C#CCNC(=O)CCl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(CCl)NCC#Cc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-N-prop-2-ynyl-acetamide (385 mg; 2.93 mmol) and 4-chloro-6-iodoquinazoline (850 mg; 1 equiv.) were dissolved in dry THF and diisopropylamine (296 mg; 0.41 ml; 1 equiv.). To this mixture was added 0.04 equivalents of copper iodide (22 mg) and Pd(PPh3)2Cl2 (82 mg). The reaction was stirred at room temperature under a nitrogen atmosphere overnight (−20 hrs). The solvent was then removed in vacuo and the residue dissolved in CH2Cl2. This solution was transferred to a separatory funnel and washed with 1× saturated NH4Cl, brine, dried over Na2SO4 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 1:1 hexlEtOAc and collecting fractions with an Rf=0.25. This yielded the 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide as an off white solid (454 mg; 53%). 1H NMR (400 MHz; CDCl3) δ 4.12 (2H, s), 4.40 (2H, d, J=5.2 Hz), 7.91-7.93 (1H, dd, J=2, 6.8 Hz), 8.00 (1H, d, J=8.4 Hz), 8.34 (1H, d, J=1.8 Hz), 9.03 (1H, s). Irms (M+): 294.0, 296.0, 298.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[Br:23])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn(C)c(=O)c(C)c1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent) in DMF is added NBS (1.20 equivalents) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.