Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[NH2:37])[N:28]=1)=[O:26]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[N:37]=[CH:14][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH2:12][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)([CH3:21])[CH3:22])[N:28]=1)=[O:26]
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(Cl)cc4c3OCC4)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 160 mg (0.47 mmol) of 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is reacted with 116 mg (0.57 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 1.0 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%), 110 mg (45% of theory) of the product is obtained.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10]1>CS(C)=O>[O:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:4]1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)NC[C@@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CCO4)CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A mixture of 60% sodium hydride (6.0 mmol), trimethyloxo sulfonium iodide (6.1 mmol) was stirred for 30 minutes and (R)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (4.80 mmol) in DMSO (20 ml) was stirred for 75 hour at the room temperature. The reaction mixture was poured on ice water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuum to provide crude compound. The crude compound was purified over silica gel column to provide title compound in 20% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH2:7])=[O:6].[C:14](=O)([O-])[O-].[Cs+].[Cs+].S(OC)(OC)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH:7][CH3:14])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1cc(F)cc([N+](=O)[O-])c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CNC(=O)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.3 %

Procedure:
To a solution of 3-fluoro-5-nitrobenzamide (1.0 g, 5.43 mmoL) in DMF (17 mL) was added cesium carbonate (2.6 g, 8.14 mmoL) and dimethyl sulphate (547 mg, 4.34 mmol) and the reaction mixture was stirred at RT for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-fluoro-N-methyl-5-nitrobenzamide (0.800 g, 80%) as a solid. Observed mass (M−1): 196.9.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C=O)C>[CH:21]1([CH2:20][O:12][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[CH:1]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Oc1ccc2c(c1)CCCCC2
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc2c(cc1OCC1CCCCC1)CCCCC2
Temperature: 60 °C

Procedure:
To a mixture of 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (Helvetica Chimica Acta 1947, 1883.) (9.9 g, 61.0 mmol) and Cs2CO3 (26.3 g, 73.2 mmol) in DMF (100 ML) was added (bromomethyl)cyclohexane (10.2 mL, 73.2 mmol). The mixture was heated to 60° C. for 18 h, dumped into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a solid. The solid was recrystallized from ethanol (13.0 g, 83%). m.p. 62-63° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[O:34]>CN(C=O)C>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2=[O:34])[CH:4]=1
Reactant: O=C1CCCCC1Cl
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC1CCCCC1=O
Reaction time: 96 h
Yield: 13.1 %

Procedure:
A suspension of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (6.4 g, 20 mmoles) and potassium carbonate (13.8 g, 0.1 mole) in DMF (34 ml) and 2-chlorocyclohexanone (3.8 g, 28.6 mmoles) was stirred for 4 days, followed by partition between water and methylene chloride. The organic phase was washed well with water, dried and concentrated. The residue was chromatographed on deactivated silica using methylene chloride (100), methanol (4), ammonia (0.5) as the solvent system. The appropriate fractions were combined and further purified by low pressure liquid chromatography to give 1.0 g of the title compound as a colorless foam. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ8.4 (bs, 1H); 8.16 (s 1H); 6.14 (s, 1H); 4.7 (m, 1H); 4.3 (s, 2H); 3.56 (q, J=7.2 Hz, 2H); 2.62 (m, 6H); 2.3-1.4 (m, 8H); 1.04 (t, J=7.2 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:26][CH:12]([C:10]1[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:11]=1)[CH3:13]
Reactant: CC(O)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(Br)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (444 mg, 1.23 mmol) and carbon tetrabromide (613 mg, 1.85 mmol) in tetrahydrofuran (5 mL) at 0° C. was added triphenylphosphine (485 mg, 1.85 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (4%→6% EtOAc/Hex) to give 284 mg (55%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.27 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 5.90 (q, J=7.0 Hz, 1H), 5.77 (qAB, JAB=10.4 Hz, 2H), 3.68 (m, 2H), 2.23 (d, J=7.0 Hz, 3H), 0.95 (m, 2H), −0.03 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 146.4, 134.2, 124.9, 124.7 (q, J=32 Hz), 124.6 (q, J=273 Hz), 121.6, 119.7 (q, J=4.8 Hz), 119.3 (q, J=2.9 Hz), 82.2, 68.1, 43.7, 25.5, 18.0, −1.4.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH2:32]1[CH2:36]OC[CH2:33]1.CO>[OH-].[Na+]>[CH2:31]([O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1)[CH2:33][CH2:32][CH3:36]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2cccc(OC)c2)CC1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc(OC)c3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester (2.61 g, 5.34 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1 g (41%); brown solid; mp 175° C.; MS: 462.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12]([OH:18])=[N:13][CH:14]=[CH:15][C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6].Br[CH2:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23](C(OC(C)(C)C)=O)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:18])[N:13]([CH2:20][C:21]3[C:29]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:23][N:22]=3)[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccnc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccn(Cc3n[nH]c4ncccc34)c2=O)c1
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-chloro-5-[(4-chloro-2-hydroxypyridin-3-yl)oxy]benzonitrile (150 mg, 0.534 mmol) in DMF (3 mL) was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (167 mg, 0.534 mmol) and potassium carbonate (73.8 mg, 0.534 mmol) and the mixture warmed to 55° C. for 60 minutes. After this time, the reaction mixture was purified by preparative HPLC using a Luna reverse phase column (10μ, C18, 250×21.2 mm) and eluting with a gradient of 5-95% ACN/water (0.5% TFA). The desired fractions were combined and the solvent evaporated in vacuo. The residue was dissolved in TFA (10 mL) and allowed to stand at room temperature for 15 minutes and then the solvent was evaporated in vacuo to give a white solid. This solid was suspended in ACN (10 mL) and the solvent evaporated in vacuo to give the title compound. 1H NMR (DMSO-d6) δ=13.64 (s, 1H), 8.52 (dd, 1H, J=1.6 and 4.5 Hz), 8.15 (dd, 1H, J=1.4 and 8.06 Hz), 7.90 (d, 1H, J=7.5 Hz), 7.73 (dd, 1H, J=1.7 and 1.4 Hz), 7.50 (dd, 1H, J=2.5 and 1.2 Hz), 7.41 (dd, 1H, J=3.2 and 1.9 Hz), 7.18 (dd, 1H, J=4.5 and 8.06 Hz), 6.61 (d, 1H, J=7.5 Hz) and 5.48 (s, 2H) ppm. HRMS (M+1): 412.0372.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH:21]3[C:33](=[O:37])[NH:34][C:35](=[O:36])[CH:20]3[C:19]=2[C:18]2[CH:17]=[C:16]([O:38][CH3:39])[CH:15]=[CH:14][C:13]1=2)(C(C)(C)C)(C)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.Cl>C1COCC1.CO>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[C:21]3[C:33](=[O:37])[NH:34][C:35](=[O:36])[C:20]=3[C:19]=2[C:18]2[CH:17]=[C:16]([O:38][CH3:39])[CH:15]=[CH:14][C:13]1=2
Reactant: COc1ccc2c(c1)c1c(n2CCCO[Si](C)(C)C(C)(C)C)CC(c2ccccc2OC)C2C(=O)NC(=O)C12
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4OC)cc1n2CCCO)C(=O)NC3=O
Yield: 72 %

Procedure:
The reaction of 6-(3-{[tert-Butyl(dimethyl)silyl)oxy}propyl)-9-methoxy-4-(2-methoxyphenyl)-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-dione (IV; Ar=2-methoxyphenyl; R10═CH2CH2CH2OSiMe2t-Bu) prepared as described in example 52 with DDQ using the procedure described in example 70 followed reaction with 2N HCl in THF/methanol gave 6-(3-Hydroxypropyl)-9-methoxy-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-methoxyphenyl, R10═CH2CH2CH2OH) (100) in a 72% yield as an orange powder; mp 223–225° C. 1H NMR δ [(CD3)2SO] 10.99 (br s, 1H), 8.53 (d, 2.6 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.45–7.40 (m, 1H), 7.36 (dd, J=7.4, 1.7 Hz, 1H), 7.29 (dd, J=8.9, 2.7 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.06 (dd, J=7.2, 7.2 Hz, 1H), 4.63 (t, J=4.8 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 3.90 (s, 3H), 3.69 (s, 3H), 3.40 (m, 2H), 1.91 (m, 2H). Found: C, 69.55; H, 5.31; N, 6.30. C25H22N2O5 requires C69.76; H, 5.15; N, 6.51.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:17][CH:16]=[CH2:15])=[O:13]
Reactant: O=C(O)CCCCCCCCCCS
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCOC(=O)CCCCCCCCCCS
Yield: 77.2 %

Procedure:
1.09 g (5 mmol) 11-mercaptoundecanoic acid was placed along with 3 g (51.7 mmol) allyl alcohol, 0.57 g p-toluenesulfonic acid and 40 ml benzene in a round bottom flask and heated for 25 minutes with azeotropic removal of water using a Dean-Stark apparatus. The reaction mixture was then cooled and washed with 10% aqueous sodium bicarbonate solution (3×20 ml). The benzene layer was dried over anhydrous MgSO4, and removal of solvent yielded a colorless oil (0.997 g, 77%). 1H-NMR (300 MHz, CDCl3) 1.27, m, 12 H; 1.60, m, 5 H; 2.33, t, 2 H, J=7.5 Hz; 2.51, q, 2 H, J=7.4 Hz; 4.59, dt, 2 H, J=5.7, 1.4 Hz; 5.20-5.39, m, 2 H; 5.85-6.00, m, 1 H; IR (film) 2560 (SH), 1730 (C=O), 1640 cm-1 (C=C); EI-MS; 258 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH:15]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH:11]=3)[CH:5]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(N)cc1C1=CCN(C)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1C1=CCN(C)CC1

Procedure:
The title compound (E129) was prepared from 4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylamine (free base of D39) (107 mg; 0.49 mmol) and 4-bromobenzenesulfonylchloride (125 mg, 0.49 mmol) using the method of Example 1 (179 mg, 77%) MH+=437/439.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:4]=1.O=P(Cl)(Cl)[Cl:23].C(N(CC)C(C)C)(C)C>C(Cl)CCl>[Cl:23][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC2CCOCC2)c2c(=O)[nH]cnc2c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 100 °C

Procedure:
A mixture of 7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4(3H)-one (0.60 g, 2.17 mmol), POCl3 (0.5 mL), and N,N-diisopropylethylamine (1.5 mL) in ClCH2CH2Cl (6 mL) was heated at 100° C. for 4 hours. After the solvent and reagents were evaporated under reduced pressure, toluene was added to the residue, and the solution was evaporated under reduced pressure. The residue was dried under vacuum to afford 4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline as a brown solid. LC-MS (ESI) m/z 295 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:25][C:26]1[C:27]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:28][C:29]([CH3:41])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[Cl:25][C:26]1[C:27]([S:42]([CH3:45])(=[O:43])=[O:44])=[CH:28][C:29]([CH3:41])=[C:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=4[CH3:24])[C:15]([NH:17][CH:18]4[CH2:19][CH2:20]4)=[O:16])=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)[CH:31]=1
Reactant: Cc1cc(S(C)(=O)=O)c(Cl)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3cc(Cl)c(S(C)(=O)=O)cc3C)nncc2c1

Procedure:
This material was prepared according to the procedure similar to that described in Method A-Example 3a, using 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide and 2-(5-chloro-2-methyl-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS (ESI, pos. ion) m/z: 506.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:32]([NH2:34])=[O:33])[CH:3]=1.C=O.[OH-].[Na+].[C:39](OCC)(=[O:41])C>COCCOC>[OH:41][CH2:39][NH:34][C:32]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=1)=[O:33]
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 4-methyl-5-[[[4-(trifluoromethoxy)phenyl]sulfonyl](2,3,6-trifluorophenyl) methyl]pyridine-2-carboxamide (177 mg, 0.350 mmol) in ethylene glycol dimethyl ether (3 ml), an aqueous solution of formaldehyde (37%, 78.9 μl) and 1 N aqueous sodium hydroxide (17.5 μl) were added at room temperature, and the mixture was stirred for 2 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and diethyl ether, and then was collected by filtration, to obtain the title compound (59.4 mg, 0.111 mmol, 32%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[H-].[Na+].[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C1COCC1>[CH3:21][O:20][C:18](=[O:19])[CH:17]([C:11](=[O:12])[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][C:2](=[O:3])[CH3:1])[C:16]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(=O)c1ccccc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of O-acetylsalicyloyl chloride (Alfa Aesar, 1.0 g, 5.05 mmol) in THF (10 mL) at 0° C. was added sodium hydride (60% dispersed in mineral oil, 263 mg, 6.57 mmol). It was stirred at 0° C. for 15 min prior to the addition of a solution of dimethyl malonate (0.67 g, 5.05 mmol) in THF (5 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 min and then at rt for 2.5 h, and was concentrated. The residue was taken up in water (50 mL), acidified by 1 N HCl aqueous solution, and extracted with EtOAc (2×100 mL). Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the intermediate (2-(2-acetoxy-benzoyl)-malonic acid dimethyl ester) (1.45 g) as an oil. The intermediate (1.26 g, 4.28 mmoL) was treated with (1/1) MeOH/10% aq HCl (26 mL) and heated to 75° C. (oil bath temperature) for 30 min and then at rt overnight. White precipitate formed during the reaction was collected, rinsed with water and dried in vacuo to give the title compound (555 mg). MS ESI(+) m/e: 221 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:25]([O-])=O)[CH:9]=2)[N:4]=1.ClC1C2C(=CC=C([N+]([O-])=O)C=2)N=C(CCl)[N:30]=1.C(OC1C=CC(NC)=CC=1)(C)C.C(Cl)Cl>CC(O)C.Cl>[NH2:30][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:25])[CH:9]=2)[N:4]=1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)nc(Cl)c2c1
Reactant: CC(C)Oc1ccc(N(C)c2nc(CCl)nc3ccc([N+](=O)[O-])cc23)cc1
Agent: CNc1ccc(OC(C)C)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(N(C)c2nc(CN)nc3ccc(N)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
(2-Chloromethyl-6-nitro-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine: A suspension of 4-chloro-2-chloromethyl-6-nitroquinazoline (200 mg, 0.77 mmol) and (4-isopropoxy-phenyl)-methyl-amine (140 mg, 0.84 mmol) in i-PrOH (1.5 mL) was treated with HCl (12 M, 6 drops) and stirred at rt overnight. CH2Cl2 was added and the reaction washed with 5% NaOH, dried (MgSO4), filtered and concentrated. The residue was purified by gradient MPLC (SiO2, EtOAc/hexanes, 0-100%) to provide 203 mg (71%) of the title compound. 1H NMR (DMSO-d6) δ 8.35 (dd, 1H), 7.86 (dd, 1H), 7.71 (dd, 1H), 7.32-7.40 (m, 2H), 7.08-7.12 (m, 2H), 4.78 (s, 2H), 4.71 (sept, 1H), 3.63 (s, 3H), 1.31 (d, 6H); LC-MS (ESI+; 387 ([M+H]+)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].CCN(CC)CC>CN(C=O)C.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][Si:10]([C:13]#[C:14][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(N)nc1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 75.7 %

Procedure:
A mixture of commercially available 2-amino-5-bromopyridine (50.0 g, 289 mmol), trimethylsilylacetylene (112 mL, 809 mmol), Et3N (120 mL, 867 mmol), PdCl2(PPh3)2 (4.06 g, 2 mol %) and PPh3 (1.52 g, 2 mol %) in DMF (290 mL) was purged for 10 min with argon. Then CuI (340 mg, 1 mol %) was added and the reaction mixture was heated up to 90° C., stirring was continued at 90° C. for 4.5 h. Cooled to 23° C., the reaction mixture was concentrated in vacuum to remove all volatiles, poured the residue onto water (300 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water (300 mL) and brine (2×250 mL), dried over MgSO4. Removal of the solvent in vacuum left a dark brown residue which was purified by flash chromatography with n-heptane and acetone to give the title compound as a brown solid (41.65 g, 76%). MS (ISP) 191 [(M+H)+].