Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)C(C)=O.C[O-].[Na+].C(O)(=O)C>CO>[NH2:1][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cc2c(cc1[N+](=O)[O-])OCO2
Yield: 95.1 %

Procedure:
40 g of 5-acetamino-6-nitro-1,3-benzodioxole were dissolved with heating in 4 l of methanol in a 10 round flask equipped with a reflux condenser. To this hot solution was added a boiling solution of 40 g of sodium methoxide in 4 l of methanol and the mixture was boiled under reflux for exactly 15 minutes. Then, the reaction was interrupted by adding 220 ml of glacial acetic acid. The methanol was removed by distillation and the last traces thereof, together with the glacial acetic acid, were removed by a two-fold evaporation with toluene. The product went into solution with 3 l of methylene chloride and could be freed from the organic residues by suction filtration. The methylene chloride solution was filtered through silicon dioxide and evaporated in vacuo. The residue, recrystallized from isopropanol, gave 30.9 g (95% of theory) of 5-amino-6-nitro-1,3-benzodioxole of melting point 203°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[F:21][C:22]1[CH:23]=[C:24]([CH:29]([OH:33])[C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:30](=[O:31])[CH:29]([C:24]2[CH:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[CH:23]=2)[OH:33])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Product: CCCC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester was coupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.7, 13.8, 19.0, 19.1, 26.0, 35.3, 35.7, 53.0, 53.2, 53.3, 61.2, 61.3, 73.3, 73.4, 103.5, 103.7, 106.1, 106.3, 109.6, 109.8, 110.1, 131.6, 131.8, 137.0, 137.1, 144.0, 161.9, 164.3, 169.3, 169.6, 171.9, 172.0, 172.5; MS 453.20 m/z (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:5]=1
Reactant: COC(OC)c1cccc(O)c1
Reactant: Clc1cnccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1cccc(Oc2cnccn2)c1
Temperature: 60 °C

Procedure:
A solution of 168 mg of 3-hydroxybenzaldehyde dimethyl acetal in 10 ml of anyhydrous dimethylformamide was stirred under nitrogen and 220 mg of potassium tert-butoxide were added. The mixture was heated at 60° C. for 1 hour, then cooled to room temperature and 115 mg of 2-chloropyrazine were added in portions. The mixture was then heated at 160° C. for 18 hours. After cooling 15 ml of water were added and the product was extracted with 50 ml of ethyl acetate. The extract was washed with 25 ml of 1M sodium hydroxide solution and 25 ml of brine and then dried over anhydrous magnesium sulphate. After filtration and evaporation of the filtrate the residual yellow oil was purified by column chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution to give 3-(2-pyrazinyloxy)-benzaldehyde dimethyl acetal as a yellow oil.
Reaction SMILES: [Mg].[Br:2][CH:3]1[CH2:5][CH2:4]1.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=O)=[CH:10][CH:9]=1.[Cl-].[NH4+]>C1COCC1>[Br:2][CH2:3][CH2:4][CH2:5][C:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=2)[CH2:12][CH2:13][CH:14]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: BrC1CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCCBr)=CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 597.7 %

Procedure:
To a suspension of magnesium (2.9 g) in THF (100 ml) was added bromocyclopropane (14.4 g, 11.9 mmol) dropwise at 0° C. under argon atmosphere. The mixture was stirred for 30 minutes at room temperature and then a solution of 7-methoxy-1-tetralone (15 g, 85.1 mmol) in THF (50 ml) was added. The mixture was refluxed for 2 hours and then cooled. Saturated aqueous ammonium chloride was introduced and the product was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in acetic acid (100 ml) and 20% hydrobromic acid (75 ml) was added. The mixture was stirred for 15 hours at room temperature and then concentrated. To the residue was added saturated aqueous sodium hydrogen bicarbonate and the product was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent removed in vacuo. The residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:9) to afford the titled compound (20 g, yield 84%, oil).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[NH:23][N:22]=C(C2C=CC(OC3C=CC=CC=3)=CC=2)[C:20]=1[C:37]#[N:38]>>[NH2:18][C:19]1[NH:23][N:22]=[C:13]([C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:20]=1[C:37]#[N:38]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)n[nH]c1N

Procedure:
The desired product was prepared from 4-(benzyloxy)benzoic acid according to the procedures similar to those (step 1 to 3) for 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.50-7.44 (m, 2H), 7.44-7.37 (m, 2H), 7.36-7.32 (m, 1H), 7.11 (d, J=7.2 Hz, 2H), 6.39 (br s, 2H) and 5.16 (s, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1c(F)cccc1NCC(C)(C)NC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(F)cccc1N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)CBr
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
1.4 ml of bromoacetyl bromide (16.1 mmol) was added to a solution of 3.97 g of [1,1-dimethyl-2-(3-fluoro-2-methylphenylamino)ethyl]carbamic acid t-butyl ester obtained in Example (67a) (13.4 mmol) in N,N-dimethylacetamide (67 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 4.23 g of the title compound (yield: 76%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:17]3[CH2:18][CH2:19][N:20]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(c1ccc(-c2cccc(Cl)c2)cc1)C1CCNCC1
Reactant: Clc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc(-c2cccc(Cl)c2)cc1)C1CCN(c2ncccn2)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
(3′-Chloro-biphenyl-4-yl)-piperidine-4-yl-methanone hydrochloride (2, 23.4 kg, 69.6 mol), 2-chloropyrimidine (8.9 kg, 1.3 equiv), and 325-mesh potassium carbonate (25 kg, 3 equiv) were mixed in acetonitrile (211 L) in a 100-gallon reactor. The batch was heated with agitation at 55-65° C. for 16 h. The batch was then cooled to 20-30° C., followed by the addition of water (70 L) and further stirred for 15 min. The batch was transferred to a 300-gallon reactor and rinsed with water (360 L) to afford a thick white suspension. After stirring for 2 h, the batch was filtered and washed with water (2×70 L) and dried to constant weight at 45-55° C. to afford crude compound 3 (23.5 kg, 89.5% yield, >99% purity) as a white crystalline solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[K].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>CN(C=O)C>[C:3]1([CH2:2][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1cccc2ccccc12
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc2ccccc12
Yield: 98.8 %

Procedure:
To a solution of 1-chloromethyl-naphthalene (8.83 g, 50 mmol) in DMF (90 mL) was added phthalimide potassium salt (11.1 g, 60 mmol). The resultant solution was stirred at 100° C. overnight. The mixture was poured into ice-cold water and the precipitate was collected, washed with small amount of methanol and dried under vacuo to give 2-naphthalen-1-ylmethyl-isoindole-1,3-dione 52 (14.2 g, 99% yield). This material was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:15][S:14][C:10]1[N:9]=[C:8]([C:7]2[C:2]([O:23][C:20]3[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CSc1nccc(-c2cccnc2Cl)n1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Temperature: 130 °C

Procedure:
A resealable pressure bottle was charged with 4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (2.85 g, 12.00 mmol), 4-aminophenol (1.44 g, 26.5 mmol), and cesium carbonate (1.44 g, 13.20 mmol). These reagents were suspended in DMSO (24 ml, 0.50 M), and the vessel was sealed and mixture heated to 130° C. for 48 h. The reaction mixture was allowed to cool to RT, diluted with water and extracted with ethyl acetate. The organic layer was collected, dried with Na2SO4, filtered, and concentrated to give light brown residue, which was purified by silica gel chromatography (ISCO, 10% to 50% Ethyl Acetate/Hexanes) to afford 4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)benzenamine as a light yellow solid. MS m/z=311 [M+H]+. Calc'd for C16H14N4OS: 310.37.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][C:5]1[NH:9][C:8]([C:10](O)=[O:11])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][C:5]1[NH:9][C:8]([C:10]([Cl:18])=[O:11])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(CCC(F)(F)F)[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(CCC(F)(F)F)[nH]1
Yield: 83.1 %

Procedure:
5-(3,3,3-trifluoropropyl)-1H-pyrrole-2-carboxylic acid (5.55 mmol, 1.15 g) in CH2Cl2 (10 ml) was treated with oxalyl chloride (16.7 mmol, 1.5 ml), then DMF (1 drop). The solution was heated to reflux for 1 h, then concentrated under reduced pressure to provide 5-(3,3,3-trifluoropropyl)-1H-pyrrole-2-carboxylic acid chloride (1.04 g). 1H NMR (CDCl3) δ 10.25 (1H, br s), 7.12 (1H, dd, J=4.0, 2.6), 6.12 (1H, dd, J=3.8, 2.7), 3.05-2.88 (2H, m), 2.59-2.41 (2H, m).
Reaction SMILES: Br.C(O)(=O)C.CS(O)(=O)=O.C(OC([NH:21][CH2:22][CH2:23][C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:35])[NH2:34])=[CH:29][C:28]=1[C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25])=O)C1C=CC=CC=1>C(OCC)C>[NH2:21][CH2:22][CH2:23][C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:34])[NH2:35])=[CH:29][C:28]=1[C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25]
Reactant: N=C(N)c1ccc(OC(=O)CCNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2)c1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: N=C(N)c1ccc(OC(=O)CCN)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To 4.0 ml of a 30% hydrogen bromide-acetic acid mixture, was added 1.0 g of 4-amidino-2-benzoylphenyl 3-benzyloxycarbonylaminopropionate methanesulfonate. The mixture was stirred for one hour at room temperature to dissolve the crystals, forming a homogeneous yellow solution. Anhydrous ethyl ether was added to the solution to precipitate a white or pale yellow powder. After removing the supernatant, the residue was washed a few times with ethyl ether to obtain 0.5 g of a hydroscopic powder of 4-amidino-2-benzoylphenyl 3-aminopropionate dihydrobromide.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][O:7][CH2:8][C:9]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][OH:11].N1C=CC=CC=1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:44][C:34]1[CH:39]=[CH:38][C:37]([S:40]([O:11][CH2:10][C:9]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][O:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:26])([F:27])[F:1])[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CC(CO)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(C)(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)cc1
Temperature: -20 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
3-(3,5-bis(trifluoromethyl)benzyloxy)-2-methyl-2-phenylpropan-1-ol (1.72 g, 4.39 mmol) was mixed with pyridine (1.39 g, 17.6 mmol) in anhydrous methylene chloride (20 ml) and cooled to −20° C. Solid p-toluenesulfonyl chloride (3.35 g, 17.6 mmol) was added in one portion and the mixture was warmed up naturally to room temperature and stirred overnight. The mixture was then loaded directly onto silica column and eluted with 5% ethyl aceta in hexanes. 1.89 g (79%) of the desired product was obtained. 1H NMR (500 MHz, CDCl3) δ: 1.37 (s, 3 H) 2.38 (s, 3 H) 3.66 (d, J=2.75 Hz, 2 H) 4.21 (d, J=9.46 Hz, 1 H) 4.27 (d, J=9.46 Hz, 1 H) 4.52 (s, 2 H) 7.27 (m, 5 H) 7.35 (d, J=8.24 Hz, 2 H) 7.62 (s, 2 H) 7.70 (s, 1 H) 7.80 (d, J=8.24 Hz, 2 H).
Reaction SMILES: [CH:1]1([CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:26].[Na+]>CO.O>[CH:1]1([CH2:5][C:6]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:24])=[O:26])=[CH:21][CH:22]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
A solution of 2-cyclobutyl-1-(4-methylsulfanyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (90 mg, 0.266 mmol) in methanol (6 mL) was added a sodium metaperiodate (171 mg, 0.798 mmol) solution in water (3 mL). The resulting mixture was stirred for 12 h at room temperature, extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to afford 2-cyclobutyl-1-(4-methanesulfinyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (94.2 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C20H22N2O2S [M+H]+ 355.47, observed 355.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN(C(=O)OC(C)(C)C)n2cccc2)cc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 4-methoxybenzyl chloride (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 303 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:19])[C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:19][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:10]=2[O:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1OC1CCOCC1
Reactant: CN1CCN(CCCO)CC1
Product: CN1CCN(CCCOc2ccc3ncnc(Cl)c3c2OC2CCOCC2)CC1

Procedure:
Using an analogous procedure to that described in the last paragraph of the portion of Note [10] immediately above that is concerned with the preparation of starting materials, 4-chloro-6-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (1.12 g) was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine to give 4-chloro-6-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.56 g); NMR Spectrum: (CDCl3) 1.85-2.2 (m, 6H), 2.32 (s, 3H), 2.35-2.7 (m, 10H), 3.42 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 4.65 (m, 1H), 7.75 (d, 1H), 7.85 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 421 and 423.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[N:9][N:10]=2)[CH:7]=1.[SH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][OH:39]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:22]([Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:20][CH2:19][CH2:18][S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([S:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:38][OH:39])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:24])[CH3:23]
Reactant: OCc1ccccc1S
Reactant: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Br)cn12)(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Sc3ccccc3CO)cn12)(C(C)C)C(C)C
Temperature: 111 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
To a solution of aryl bromide of Example 7 (50.7 g, 0.10 moles) in toluene (250 ml) was added (2-sulfanylphenyl)methanol (16.8 g, 0.12 moles), sodium (tert)-butoxide (14.4 g, 015 moles) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (II) (0.41 g, 0.0005 moles). The resultant mixture was sparged with nitrogen for 10 minutes then heated at 111° C. for 16 hours. The reaction was cooled to 20° C., diluted with isopropyl acetate (200 ml) and washed with 2M hydrochloric acid solution (250 ml). The aqueous phase was extracted with isopropyl acetate (50 ml) and the combined organics were washed sequentially with 1M sodium hydroxide solution (250 ml) and 10% w/w sodium chloride solution (250 ml). The solvent was distilled under reduced pressure and replaced with (tert)-butyl methyl ether to give a final volume of 250 ml. The solution was cooled to 5° C. and granulated for 5 hours, then solid was collected by filtration to give the title compound as a white solid (38.5 g, 68%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH2:22][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27]
Reactant: C1CCNC1
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5)c4)cc23)CCS1(=O)=O
Yield: 17.6 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid, and pyrrolidine (0.058 mL, 0.697 mmol) was added. Stirred for 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring overnight at 23° C. The mixture was quenched with water, extracted with DCM, the DCM solution was evaporated to dryness, and the resulting mixture was rerun through the same process: 1.5 mL of DMSO, 1 drop of glacial acetic acid, and 0.577 mL of pyrrolidine. Left stirring 30 min and then 299 mg of polymer bound sodium triacetoxyborohydride was added and the mixture was left stirring 16 h. The sodium triacetoxyborohydride polymer bound was removed by filtration. The mixture was dissolved in 1 mL of DMSO, and the product was purified by preparative HPLC(NH4OH buffer). The desired fractions were concentrated, giving 6 mg of the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:18](=[O:22])([O:20][CH3:21])[NH2:19]>C(OCC)C>[CH:5]([NH:19][C:18](=[O:22])[O:20][CH3:21])=[CH:4][CH2:3][CH2:2][CH3:1]
Reactant: COC(N)=O
Reactant: CCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCC=CNC(=O)OC
Yield: 78.2 %

Procedure:
430 parts of n-valeraldehyde and 5 parts of p-toluenesulfonic acid are added in succession to a solution of 750 parts of methyl carbamate in 2,000 parts by volume of diethyl ether at 25° C. After a reaction time of one hour, in which the temperature rises to 40° C., filtration with suction and subsequent fractional distillation of the solid in the presence of 15 parts of potassium carbonate and 2 parts of hydroquinone give 559.1 parts of methyl N-(1-pentenyl)-carbamate (78.2% yield, based on n-valeraldehyde employed) as a cis/trans isomer mixture of boiling point 97°-102° C./16 mbar, and 352.5 parts of methyl carbamate, which can be re-used.