Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>CN(C)C(=O)C>[Cl:17][C:9]1[C:8]2[C:7](=[O:18])[C:6]3[C:15](=[C:2]([NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Reactant: CN(C)CCN
Solvent: CC(=O)N(C)C
Product: CN(C)CCNc1cccc2c1C(=O)c1cccc(Cl)c1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
A mixture of 1,5-dichloro anthraquinone (5.0 g, 18.0 mmol), N,N-dimethylacetamide (30 mL) and N,N-dimethylethylenediamine (2 mL, 18 mmol) was stirred at room temperature for 1 hour and then heated in an oil bath (T=100° C.) for 45 minutes. Reaction mixture was cooled and filtered. To the filtrate petroleum ether (50 mL) was added and combined mixture was stirred at 4° C. over night. Precipitated solid was removed by filtration and supernatant was evaporated to dryness, co-evaporated with chloroform and dried under vacuum. The crude dye was then purified on Biotage SP4 system using a gradient of methanol in chloroform. Appropriate fractions were combined and evaporated to dryness to provide Compound 17 (1.0 g) as a red solid. Rf (9:1 CHCl3/MeOH): 0.46; Abs (max, PBS)=500 nm. The structure of Compound 17 is given below:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([C:17]([O:19]CC)=[O:18])=[CH:11]3)=[CH:4][C:3]=1[O:22][CH2:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31].O.[OH-].[Li+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([C:17]([OH:19])=[O:18])=[CH:11]3)=[CH:4][C:3]=1[O:22][CH2:23][C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CCOC(=O)c1cc2cc(-c3cnc(N)c(OCc4c(Cl)cccc4Cl)c3)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ncc(-c2ccc3[nH]c(C(=O)O)cc3c2)cc1OCc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
To a mixture of ethyl 5-{6-amino-5-[(2,6-dichlorobenzyl)oxy]pyridin-3-yl}-1H-indole-2-carboxylate (2.5 g, 5.5 mmol) in methanol:water (60 mL:20 mL), lithium hydroxide (0.65 g, 27.1 mmol) was added. The reaction was heated to reflux for overnight. Most of the solvent was evaporated and the mixture was acidified, and stirred for 10 min. The precipitate was filtered out and washed with water to yield 5-{6-amino-5-[(2,6-dichlorobenzyl)oxy]pyridin-3-yl}-1H-indole-2-carboxylic acid as tan solid.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]([CH3:25])([CH3:24])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C(=O)C)[CH:8]=1.[OH-].[K+].C(O)C.C(OCC)(=O)C>O>[F:26][CH:2]([F:1])[C:3]([CH3:24])([CH3:25])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1
Reactant: CC(=O)N(c1ccccc1)c1cc(COCC(C)(C)C(F)F)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(COCc1ccc(F)c(Nc2ccccc2)c1)C(F)F
Reaction time: 8 h
Yield: 52 %

Procedure:
1,1-Difluoro-2,2-dimethyl-3-[3-(N-phenyl-N-acetylamino)-4fluorobenzyloxy]propane (0.5 g) was suspended in a 1 molar solution of potassium hydroxide in water containing 20% by volume ethanol and the mixture was heated at the reflux temperature for 8 hours. After standing overnight at the ambient temperature, the mixture was shaken several times with ethyl acetate and the combined organic extracts washed with water and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a brown oil which was purified by column chromatography on a silica gel supoort, eluting with petroleum ether (boiling range 40°-60° C.) containing 10% by volume ethyl acetate, to give the title compound (0.23 g) as a pale yellow oil.
Reaction SMILES: [F:1][CH:2]([CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].COCCN(S(F)(F)[F:42])CCOC>ClCCl>[F:1][CH:2]([CH:8]([F:42])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:24][CH:25]=3)[N:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(F)C(F)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To the crude ethyl 2-fluoro-3-hydroxy-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate (0.11 g, 0.26 mmol) in dichloromethane (1.7 mL) at 0° C. was added Deoxo-Fluor® (0.05 mL, 0.28 mmol) and stirred for 30 minutes. The reaction mixture was loaded onto a Celite® cartridge and purified by flash column chromatography using 0-60% ethyl acetate/hexanes as eluent to afford the title compound as a yellow oil (0.054 g, 47%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=1.9 Hz, 1H), 8.32-8.14 (m, 2H), 7.87-7.73 (m, 2H), 7.50 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.11-5.76 (m, 1H), 5.52-4.90 (m, 1H), 4.27 (dqd, J=23.6, 7.1, 2.1 Hz, 2H), 1.27 (dt, J=19.4, 7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.04, −187.64, −187.68, −192.41, −192.44, −202.56, −202.60, −204.97, −205.00; ESIMS m/z 442 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[Cl:25])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC(NN)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)=[CH:11][C:10]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[Cl:25])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CC(c3sccc3Cl)=NN2c2ccc(Cl)cc2)cc1
Agent: NNc1ccc(Cl)cc1
Product: Clc1ccc(-c2cc(-c3sccc3Cl)nn2-c2ccc(Cl)cc2)cc1

Procedure:
1,5-Bis-(4-chloro-phenyl)-3-(3-chloro-thiophen-2-yl)-4,5-dihydro-1H-pyrazole: The title compound was prepared from 3-(4-chloro-phenyl)-1-(3-chloro-thiophen-2-yl)-propenone and 4-chloro-phenylhydrazine by a procedure similar to that of Example 105a as a yellowish oil (112 mg, 51.8%). 1H NMR (CDCl3): 7.35 (d, J=8.7 Hz, 2H), 7.27 (t, 3H), 7.15 (d, J=9.3 Hz, 2H), 6.91 (m, 3H), 5.25 (m, 1H), 4.03 (m, 1H), 3.83 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[C:12]([C:13](OC)=[O:14])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH2:10][CH:9]=2)=[C:6]([CH3:20])[CH:5]=[CH:4][N:3]=1.[H-].C([Al+]C(C)C)(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH3:1][C:2]1[C:7]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH2:10][CH:9]=2)=[C:6]([CH3:20])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)C1=C(C(C)C)CC=C1c1c(C)ccnc1C
Agent: CC(C)[Al+]C(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccnc(C)c1C1=CCC(C(C)C)=C1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of methyl 5-(2,4-dimethyl-3-pyridinyl)-2-(1-methylethyl)-1,4-cyclopentadiene-1-carboxylate (0.17 g, 0.62 mmol) in THF (1.7 mL) was stirred at 0° C. as a 1.5 M solution of diisopropylaluminum hydride in toluene (0.88 mL, 1.32 mmol) was added. The solution was allowed to warm to room temperature and stir overnight. The solution was then cooled to 0° C. before adding additional portion of diisopropylaluminum hydride in toluene (0.88 mL, 1.32 mmol). The solution was allowed to stir overnight before the addition a 10% aqueous solution of Rochelle's salt. The solution was then allowed to stir overnight. The solution was extracted with ethyl acetate and the organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, dichloromethane to 19:1 dichloromethane:methanol) to yield [5-(2,4-dimethyl-3-pyridinyl)-2-(1-methylethyl)-1,4-cyclopentadien-1-yl]methanol (98 mg, 64%). 1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J=5 Hz, 1H), 7.18 (d, J=5 Hz, 1H), 4.87 (t, J=5 Hz, 1H), 4.04 (d, J=5 Hz, 2H), 3.34 (septet, J=7 Hz, overlapping water), 2.18 (s, 3H), 2.02 (s, 3H), 1.30 (d, J=7 Hz, 6H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:31]=[C:30]([CH3:32])[O:29][C:28]=1[C:33]([F:36])([F:35])[F:34])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:31]=[C:30]([CH3:32])[O:29][C:28]=3[C:33]([F:36])([F:34])[F:35])[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(N=C=O)c(C(F)(F)F)o1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cc(C)oc3C(F)(F)F)c(=O)n(C3CCCC3)c12
Yield: 54.4 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(5-methyl-2-trifluoromethyl-furan-3-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (25 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 3-isocyanato-5-methyl-2-trifluoromethyl-furan (0.5 mmol) following general procedure C. LCMS: m/z 460 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11](C(OC(C)(C)C)=O)[CH:12]=2)=[CH:4][CH:3]=1.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([O:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:31]([CH:34]=2)[C:32]#[N:33])[CH:24]=[CH:23][N:22]=1>>[NH:11]1[CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:23]3[CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:35][CH:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[C:31]([CH:34]=4)[C:32]#[N:33])[CH:26]=[CH:21][N:22]=3)=[N:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(N)nc2)cn1
Reactant: N#Cc1cc(-c2ccnc(Cl)c2)ccc1OC1CCOCC1
Product: N#Cc1cc(-c2ccnc(Nc3ccc(-c4cn[nH]c4)cn3)c2)ccc1OC1CCOCC1
Yield: 16 %

Procedure:
85 mg of tert-butyl 4-(6-aminopyridin-3-yl)pyrazole-1-carboxylate are reacted with 100 mg of 5-(2-chloropyridin-4-yl)-2-(tetrahydropyran-4-yloxy)benzonitrile in accordance with the above-mentioned general procedure for the Buchwald-Hartwig reaction, giving the desired product in 16% yield;
Reaction SMILES: [O:1]=[C:2]([C:14]1[S:21][C:20]([CH3:22])=[C:19]2[C:15]=1[CH2:16][C@H:17]1[C:23]([CH3:25])([CH3:24])[C@H:18]12)[CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1>C(O)C.C1COCC1.[Pd]>[O:1]=[C:2]([C:14]1[S:21][C:20]([CH3:22])=[C:19]2[C:15]=1[CH2:16][C@H:17]1[C:23]([CH3:25])([CH3:24])[C@H:18]12)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1
Reactant: Cc1sc(C(=O)C=Cc2ccc(C(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc(C(=O)CCc2ccc(C(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-benzoic acid (780 mg, 2.21 mmol), Pd/C (250 mg, 10% Pd) in ethanol (50 mL) and THF (10 mL) is stirred at rt for 2 h under 1.5 bar H2. The reaction mixture is filtered, the filtrate is evaporated and the crude product is purified by CC on silica gel eluting with EA to give 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-benzoic acid (751 mg) as a colourless foam; LC-MS: tR=1.04 min, [M+1]+=355.08; 1H NMR (CDCl3): δ 8.02 (d, J=7.6 Hz, 2H), 7.32 8d, J=7.6 Hz, 2H), 3.12-2.90 (m, 5H), 2.77 (d, J=18.8 Hz, 1H), 2.37 (s, 3H), 1.92-1.86 (m, 2H), 1.11 (s, 3H), 0.69 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccccc1
Product: CCc1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCC(=O)O
Reactant: CCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCC(=O)NCC(=O)O
Yield: 79.5 %

Procedure:
Glycine (20 mmol) was reacted with nonanoyl chloride (22 ml) in the presence of NaOH (40 mmol) in a mixture of water and ether as described in Example 1 Part A. The crude crystalline product (4.25 g) was recrystallized from ethyl acetate (40-50 ml) to give the title compound (3.42 g, 79.5%), m.p. 106°-109° C.
Reaction SMILES: S([O-])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.[Na+].[OH2:19]>>[C:5]([OH:19])(=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: O
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
Example 1 is illustrated by FIG. 1. The thermally-insulated vessel B1 contains an emulsion whose continuous phase consists of 10 metric tons of water containing 1% by weight of a surface-active agent consisting of sodium lauryl sulfate; the dispersed phase of the emulsion is formed of 10 metric tons of stearic acid whose melting point is 69° C. The volume of the emulsion is 21.76 m3 at 80° C. and 20.62 m3 at 60° C. in view of the difference of the volumic mass of stearic acid.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH3:49])[CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][C:15]([C:19]3[CH:20]=[CH:21][C:22]4[NH:23][C:24]5[C:29]([C:30]=4[CH:31]=3)=[CH:28][C:27]([C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:37]6[C:42]([C:43]=4[CH:44]=3)=[CH:41][CH:40]=[CH:39][CH:38]=6)=[CH:26][CH:25]=5)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[CH2:50](Br)[CH:51]=[CH2:52]>CS(C)=O>[CH3:3][CH:4]([CH3:49])[CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][C:15]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH2:52][CH:51]=[CH2:50])[C:24]5[C:29]([C:30]=4[CH:31]=3)=[CH:28][C:27]([C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:37]6[C:42]([C:43]=4[CH:44]=3)=[CH:41][CH:40]=[CH:39][CH:38]=6)=[CH:26][CH:25]=5)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CC(C)Cn1c2ccccc2c2cc(-c3ccc4[nH]c5ccc(-c6ccc7c(c6)c6ccccc6n7CC(C)C)cc5c4c3)ccc21
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCn1c2ccc(-c3ccc4c(c3)c3ccccc3n4CC(C)C)cc2c2cc(-c3ccc4c(c3)c3ccccc3n4CC(C)C)ccc21
Reaction time: 3 h
Yield: 50.1 %

Procedure:
A mixture of NaOH (0.1 g, 2.58 mmol) and 7 (0.26 g, 0.43 mmol) in DMSO (20 ml) was stirred at room temperature for 10 minutes before allylbromide (0.26 g, 2.13 mmol) was added in one portion. The mixture was stirred for another 3 hours before quenching with water followed by extraction with methylene chloride. The organic extracts were combined, washed with water and dried over MgSO4. Upon evaporating off the solvent, the crude product was purified by column chromatography on silica gel using hexane/methylene chloride 4:1 (v/v) as the eluent to yield 8 (0.14 g, 49%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.52-8.44 (m, 4H), 8.21-8.19 (d, 2H), 7.87-7.84 (m, 4H), 7.52-7.42 (m, 8H), 7.27-7.25 (m, 2H), 6.15-6.02 (m, 1H), 5.28-5.12 (m, 2H), 5.02-5.01 (d, 2H), 4.16-4.14 (d, 4H), 2.50-2.40 (m, 2H), 1.04-1.03 (d, 12H).
Reaction SMILES: C(ON=O)(C)(C)C.[I:8]I.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][C:20](N)=[N:21][CH:22]=2)=[CH:13][CH:12]=1.O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[N:21][C:20]([I:8])=[CH:19][N:18]=2)=[CH:13][CH:12]=1
Reactant: II
Reactant: Nc1cnc(-c2ccc(Cl)cc2)cn1
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(-c2cnc(I)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flask protected from light, 4.90 mL (40.0 mmol) of tert-butylnitrite and 7.61 g (30.0 mmol) of iodine were added to a solution of 4.80 g (23.5 mmol) of 5-(4-chlorophenyl)pyrazin-2-ylamine in 100 mL of carbon tetrachloride and 50 mL of DCM. The mixture was stirred overnight at RT and then combined with 100 mL of water. The organic phase was washed twice with 50 mL of 10% aqueous sodium thiosulfate solution and 50 mL of water, dried over magnesium sulfate, filtered through activated charcoal, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, PE→PE/EtOAc 8:2). Yield: 3.40 g (46% of theoretical); C10H6ClIN2 (M=316.525); calc.: molpeak (M+H)+:317/319 (Cl); found: molpeak (M+H)+:317/319 (Cl); Rf value: 0.55 (silica gel, PE/EtOAc 9:1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH3:31][NH:32][CH2:33][CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:32]([CH2:33][CH3:34])[CH3:31])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: CCNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: CCN(C)Cc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 44 μl of methylethylamine and 15 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 170 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]([F:13])=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:12][C:10]1[C:9]([F:13])=[C:4]([C:3]([CH3:14])=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)c(N)cc(Br)c1F
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C)c(NC2CCOCC2)cc(Br)c1F
Reaction time: 5.5 h
Yield: 82.2 %

Procedure:
To a solution of methyl 3-amino-5-bromo-6-fluoro-2-methylbenzoate (2.23 g, 8.08 mmol) in 1,2-Dichloroethane (32 ml) at room temperature and under nitrogen was added oxan-4-one (1.49 ml, 16.17 mmol) followed by acetic acid (2.78 ml, 48.5 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (5.14 g, 24.25 mmol) at room temperature. After stirring for 5.5 hours there was no unreacted starting material present by LCMS. Deionized water (32 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×32 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 6:4 Heptane:EtOAc) to give 2.3 g (82%) of methyl 3-bromo-2-fluoro-6-methyl-5-[(oxan-4-yl)amino]benzoate as a off-white solid. LC-MS 99%, 2.13 min (3 minute LC-MS method), m/z=245.9/247.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 6.78 (d, J=5.9 Hz, 1H), 4.01 (dt, J=11.9, 3.4 Hz, 2H), 3.93 (s, 3H), 3.53 (td, J=11.7, 2.1 Hz, 2H), 3.49-3.42 (m, 1H), 3.34 (s, 1H), 2.04 (s, 5H), 1.48 (qd, J=11.0, 4.2 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1>C(C(C)=O)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(=O)c1ccc(O)cc1O
Reactant: ClCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1ccc(OCc2ccsc2)cc1O
Yield: 74.1 %

Procedure:
A stirred solution of 4-(2,4-dihydroxyphenyl)-4-oxobutyric acid, methyl ester 6.76 g) in methyl ethyl ketone (150 mL) is treated with potassium carbonate (4.17 g), potassium iodide (5 g) tetrabutyl ammonium chloride (1 g) and 3-chloromethylthiophene (4 g), and refluxed for 24 hours. The reaction mixture is filtered, the filtrate is evaporated. The residue is dissolved in ethyl acetate, washed with water, dried, and evaporated. The residue is recrystallised from ethyl acetate/cyclohexane to give 4-(2-hydroxy-4-(thiophen-3-ylmethoxy)phenyl]-4-oxo-butyric acid, methyl ester (7.16 g), a pale cream solid, mp. 100-102° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH2:18][O:19][CH3:20])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH2:18][O:19][CH3:20])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COCc1onc(-c2cccc(C#N)c2)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCc1onc(-c2cccc(C#N)c2)c1C(=O)O
Reaction time: 24 h
Yield: 75.6 %

Procedure:
Methyl 3-(3-cyanophenyl)-5-(methoxymethyl)isoxazole-4-carboxylate (1.12 g, 4.1 mmol) was dissolved in 3 mL THF and 1 mL water. Lithium hydroxide monohydrate (0.20 g, 4.9 mmol) was added and the reaction was allowed to stir for 24 hours under N2. The solvent was removed in vacuo and redissolved in 100 mL of water. The resulting solution was extracted with 30 mL EtOAc twice then acidified with 1N HCl to pH 3. The acidic solution was extracted three times with 30 mL of EtOAc. The combined organic were dried with MgSO4 and concentrated in vacuo to give the desired white solid (0.80 g, 75%). 1H NMR (CDCl3) δ: 7.98 (m, 1H); 7.91 (dd, J=8.1, 2.9, 1H); 7.79 (dd, J=8.1 , 2.9, 1H); 7.59 (t, J=8.1, 1H); 4.89 (s, 2H); 3.53 (s, 3H).