Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[C:25]([O:26][CH2:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:35]([C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28](=[O:29])[CH2:27][O:26][C:25]1[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:42])=[CH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc2ccccc2cc1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cc2ccccc2cc1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of 230 mg (0.4 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml trifluoroacetic acid was stirred for 18 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 180 mg (96%) of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CCN(C(C)C)[CH:36]([CH3:38])[CH3:37].BrCCC>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[N:14]([CH2:37][CH2:36][CH3:38])[CH:15]=[C:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Solvent: ClCCCl
Solvent: CCCBr
Product: CCCn1cc(Cc2cnc(OC)nc2)c(=O)nc1SCc1ccc(Oc2ccc(F)cc2)cc1
Yield: 31.4 %

Procedure:
The same procedure as E54 from 2-((4-(4-fluorophenoxy)benzyl)thio)-5-((2-methoxypyrimidin-5-yl)methyl)pyrimidin-4(1H)-one (146.6 mg, 0.325 mmol), Hunig's base (0.171 mL, 0.976 mmol) and 1-bromopropane (80 mg, 0.651 mmol) in DCE (5 mL), except that the time was prolonged to 3 days, to afford the title compound (50 mg, 0.102 mmol, 31.2% yield). LCMS: rt=3.41 min, [M+H+]=493
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:38])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:38])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1cc(-c2ccnc3[nH]c(C4=CCNCC4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reaction time: 2 h
Yield: 42 %

Procedure:
1,1-dimethylethyl 4-{4-[1-ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-3,6-dihydro-1 (2H)-pyridinecarboxylate (0.362 mmol) was treated with 4N hydrogen chloride in 1,4-dioxane (2 mL). The suspension was stirred vigorously for 2 h, then concentrated under reduced pressure. Purification of the residue by reverse phase HPLC afforded the title compound as a yellow solid (42%). ESMS [M+H]+: 504.4
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][CH:33]=1>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:36][CH:37]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)CCc1ccc(NCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 3-(4-amino-phenyl)-propionic acid. MS (ES) m/z 552.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:14].[K+].CC[OH:18]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:18])=[O:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: [OH-]
Reactant: N#CC1(c2ccc(Br)cc2)CCC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C1(c2ccc(Br)cc2)CCC1
Yield: 79 %

Procedure:
To a solution of 1-(4-bromophenyl)cyclobutanecarbonitrile (1.0 g, 4.2 mmol) in EtOH (28 mL) and water (2 mL) was added KOH (2.1 g, 42 mmol). The reaction mixture was heated to reflux for 16 hours. The reaction was then quenched with 1M hydrochloric acid in order to adjust pH to 7. The organic solvents were removed in vacuo to give a residue, which was dissolved in ethyl acetate (40 mL), then washed with brine (3×10 mL). The organic phase was concentrated in vacuo, and the resulting oil was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=8:1) to give 1-(4-bromophenyl)cyclobutanecarboxylic acid (0.8 g, 79% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:3]([O:6][C:7]([C:9]([CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
1.69 g (70.43 mmol) of sodium hydride are added in portions to a solution of 20 g (64.03 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonylheptanedioate from Example 82A in 140 ml of dimethylformamide at 0° C. The reaction mixture is then allowed to reach room temperature and is stirred for 30 min. The reaction solution is cooled to 0° C. again and, after addition of 16.32 g (83.24 mmol) of 4-bromomethylbenzonitrile in 140 ml of DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography an silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1→1:1). 20.08 g (46.97 mmol, 73% yield) of a colorless solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]#N.S(=O)(=O)(O)[OH:24].[OH2:28]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:24])=[O:28]
Reactant: O
Reactant: N#CCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: O=S(=O)(O)O
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Temperature: 100 °C
Yield: 95 %

Procedure:
30 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile and a mixture of 46 ml of concentrated sulfuric acid and 55 ml water are heated for 2.5 hours while stirring at 100°C. Then the solution is diluted with 700 ml of water, the precipitate is drawn off and washed with water. The filter cake is dissolved in diluted sodium hydroxide and purified with active charcoal and the acid is precipitated with diluted hydrochloric acid. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained with a yield of 95 %; F 179.5°-181° (from methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:15])=[C:6]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.[CH2:16]1[CH2:26]CN2C(=NCCC2)C[CH2:17]1.BrC(C)C.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH:16]([CH3:26])[CH3:17])=[C:6]([O:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[CH:7]=1
Reactant: CC(C)(C)C(=O)Oc1cc(Br)ccc1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)Br
Product: CC(C)Oc1ccc(Br)cc1OC(=O)C(C)(C)C
Temperature: 40 °C
Yield: 60 %

Procedure:
2,2-dimethylpropionic acid 5-bromo-2-hydroxyphenylester (500 mg) was dissolved in dimethylformamide and stirred with 1,8-diazabicyclo[5.4.0]undece-7-ene (DBU; 0.32 ml) for 10 minutes. Then, 2-bromopropane (0.25 ml) was added and heated at 40° C. After the reaction was completed, water was added to dilute and extracted with ethylacetate. An organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/12, v/v). As a result, the present compound (340 mg, productive yield 60%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])#[N:2].[CH3:15][C:16]1([CH3:27])[O:21][C:20](=[O:22])[C:19](=[CH:23]OC)[C:18](=[O:26])[O:17]1>C(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:23]=[C:19]2[C:18](=[O:26])[O:17][C:16]([CH3:15])([CH3:27])[O:21][C:20]2=[O:22])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])#[N:2]
Reactant: COCCOc1cc(N)ccc1C#N
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: COCCOc1cc(NC=C2C(=O)OC(C)(C)OC2=O)ccc1C#N
Yield: 60.6 %

Procedure:
4-Cyano-3-(2-methoxyethoxy)aniline (760 mg, 4 mmol) and 2,2-dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (1.0 g, 5.4 mmol), (Montatsh. Chem. 1967, 98, 564), in ethanol (20 ml) was heated at reflux for 1 hour. The mixture was allowed to cool and the solid collected by filtration to give 5-((4-cyano-3-(2-methoxyethoxy)anilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (840 mg, 61%) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][O:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH2:5].[C:28](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.ClCCl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][O:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:5][CH3:28]
Reactant: COC(=O)[C@@H](N)COC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CC#N
Product: CN[C@@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.6 %

Procedure:
To a mixture of 0.8 g (2.2 mmol) of O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester (Example 4a, Step 2) and 1.2 g (8.9 mmol) of potassium carbonate in acetonitrile (5 mL) was added 0.17 mL (2.7 mmol) iodomethane and the mixture stirred at room temperature for 16 h. The mixture was dissolved in dichloromethane, filtered and after evaporation of the solvent the residue was chromatographed on silica gel with 60% ethyl acetate in hexanes to give 0.038 g (yield 4.5%) N-Methyl--O--(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester as an oil. 1H NMR (CDCl3, 300 MHz) δ: 7.67 (d, 2H), 7.45-7.10 (m, 11H), 3.73 (s, 3 H), 3.35-3.15 (m, 3H), 2.37 (s, 3H), 2.06 (s, 1H); 13C NMR (CDCl3, 75 MHz) 6: 173.2, 146.6, 146.4, 143.1, 140.6, 129.2, 129.1, 128.3, 128.1, 128.0, 127.1, 125.4, 125.3, 125.1, 119.9, 88.3, 63.8, 62.9, 51.7.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.C1(C)C=CC=CC=1.[OH-].[Na+]>O>[CH:1]1([C:4]2[C:5]([C:6]#[N:7])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Into a glass flask having an internal volume of 300 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 11.6 g (106.6 mmol) of 3-cyclopropyl-3-oxopropanenitrile, 31.0 g (96.9 mmol) of 2-amino-4′-fluorobenzophenone methanesulfonate having a purity of 97.3% and 121 mL of toluene were put in an atmosphere of nitrogen, and reaction was carried out under 0.04 MPa at 80° C. for 2 hours while distilling off the formed water. After completion of the reaction, the reaction liquid was cooled to room temperature, 60 mL of water and 13.3 mL (106.4 mmol) of a 8 mol/L sodium hydroxide aqueous solution were added thereto to make the reaction liquid basic, followed by liquid separation, and the obtained organic layer was analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 27.9 g (yield: 99%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: N1(CCN2CCC([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])CC2)CCCCCC1.Cl.Cl.Cl.N[CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][CH:51]([OH:54])[CH2:50][CH2:49]2)[CH2:42][CH2:41]1>>[OH:54][CH:51]1[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][N:43]2[CH2:44][CH2:45][CH:40]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:41][CH2:42]2)[CH2:49][CH2:50]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3-fluoro-phenoxy)-1H-indole-2-carboxylic acid 141 (see example 118) and amine 21.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:11])[CH:7]([OH:10])[CH2:8][CH3:9].C(Cl)Cl>C(N(CC)CC)C>[CH3:1][S:2]([O:11][CH2:6][CH:7]([O:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8][CH3:9])(=[O:4])=[O:3]
Reactant: CCC(O)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(COS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a one liter, four-necked round bottom flask equipped with stirrer, condenser, thermometer, and addition funnel, 57.0 parts of methanesulfonyl chloride, 22.5 parts of 1,2-butanediol and 57.0 parts of methylene chloride were mixed under a nitrogen blanket and cooled to 0° C. using a dry ice-acetone bath. To this 50.5 parts of triethylamine was added over one hour. The reaction was stirred at 0° C. for an additional three hours and allowed to stand for 18 hours at 0° C. The mixture was vacuum filtered and then washed successively with chilled dilute sulfuric acid (twice with 200 part-portions), dilute sodium bicarbonate (three times with 200 part-portions), and water (twice with 200 part-portions), dried over sodium sulfate, filtered, and the solvent removed in vacuo at 35° C. to give the product as a pale yellow liquid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=1)=[O:4].[OH-].[Na+]>CO.O>[CH3:10][N:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1nc2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(C(=O)O)nc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 1-methyl-1H-benzoimidazole-2-carboxylic acid methyl ester (81) (190 mg, 1.0 mmol) and NaOH (80 mg, 2.0 mmol) in MeOH/H2O (1:1, 20 mL) was stirred at 50° C. for 1 h. The mixture was concentrated, then diluted with water (15 mL), adjusted pH=2 with concentrated HCl. Then the precipitate was formed and filtered, washed with water and dried to give 1-methyl-1H-benzoimidazole-2-carboxylic acid (82) (176 mg, 1.0 mmol, yield 100%)
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>C(N(CC)CC)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: CC(=O)C(Cl)=NNc1ccc(Cl)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1ccc(Cl)cc1)Sc1ccc(Cl)cc1
Yield: 96 %

Procedure:
The reaction of 4.47 g of 1-chloro-1-[(4-chlorophenyl) hydrazono]-2-propanone with 3.43 g of 4-chlorothiophenol and 3.36 ml of triethylamine as Example 11 yielded 6.3 g of 1-[(4-chlorophenyl)thio]-1-[(4-chlorophenyl)hydrazono]-2-propanone, mp 164°-167° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.[CH3:27][O:28][C:29]1[CH:40]=[CH:39][CH:38]=[CH:37][C:30]=1[C:31](N(OC)C)=[O:32]>C1COCC1>[Br:19][C:20]1[CH:21]=[C:22]([C:31]([C:30]2[CH:37]=[CH:38][CH:39]=[CH:40][C:29]=2[O:28][CH3:27])=[O:32])[C:23]([F:26])=[N:24][CH:25]=1
Reactant: COc1ccccc1C(=O)N(C)OC
Reactant: Fc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1cc(Br)cnc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 21.9 %

Procedure:
To a round bottom flask were added di-iso-propylamine (5 ml, 35 mmol), and anhydrous THF (40 ml). The solution was stirred at −78° C. for 5 minutes under nitrogen. Then a 2.5 M solution of n-butyl lithium in hexane (12 ml, 30 mmol) was added slowly and the resulting solution was allowed to stir at −78° C. for another 30 minutes. At this time 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added dropwise and the solution was allowed to sir at −40° C. for 2 hours. Then 2, N-dimethoxy-N-methyl-benzamide (7.2 g, 37 mmol) in THF (10 ml) was added and the resulting mixture was stirred at −40° C. for another 2 hours. The reaction was then quenched with 10% citric acid (40 ml) and worked up with ethyl acetate, brine, dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded (5-bromo-2-fluoro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (1.9 g, 21% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.64 (s, 3H), 7.14 (m, 1H), 7.18 (d, 1H), 7.65 (m, 2H), 8.38 (d, 1H), 8.58 (s, 1H).). MS: m/z 310+312 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[C:16]3[CH2:21][N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[F:35])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>O1CCOCC1>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[C:16]3[CH2:21][N:20]([CH:22]4[CH2:23][CH2:24][N:25]([C:46]([O:48][CH3:49])=[O:47])[CH2:26][CH2:27]4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[F:35])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C2CCNCC2)C3)cc1F
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C2CCN(C(=O)OC)CC2)C3)cc1F
Temperature: 25 °C
Yield: 5.3 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(2-fluoro-4-(4-(3-methylmorpholino)-6-(piperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (90 mg, 0.17 mmol) and DIPEA (30 μL, 0.17 mmol) in Dioxane (5 mL) was added methyl chloroformate (14 μL, 0.19 mmol). Reaction mixture was stirred at room temperature until analysis by LCMS indicated reaction was complete. Solvent was then removed in vacuo. Purified by prep. HPLC (low pH) to afford an orange gum. This was then further purified using a TsOH cartridge to remove residual formic acid from HPLC (loaded in MeOH eluted with 2M methanolic ammonia). This gave a creamy pink solid (4.9 mg, 0.009 mmol, 5.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(-n2ccc3cc(OCCCCCCBr)ccc32)cc1
Temperature: 55 °C
Reaction time: 6 h
Yield: 68.3 %

Procedure:
2.05 g (9 mmol) 1-(4-Fluoro-phenyl)-1H-indol-5-ol in 25 ml acetone were treated with 4.7 ml (30 mmol) 1,6-dibromohexane and 4.14 g (30 mmol) K2CO3 powder in 25 ml acetone. The mixture was stirred at 55° C. for 6 h, and at RT for 20 h. Acetone was added, and the suspension filtered. Purification of the crude product with column chromatography with hexane/EtOAc 49:1 yielded 2.4 g (68%) 5-(6-Bromo-hexyloxy)-1-(4-fluoro-phenyl)-1H-indole as colorless solid, MS: 389 (M, 1Br, 1Cl).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:13]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14]1)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([SH:23])[CH3:22].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[CH2:1]([O:8][C@H:9]([C@@H:13]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14]1)[C:10](=[O:12])[S:23][CH2:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)[C@@H]([C@@H](OCc2ccccc2)C(=O)O)O1
Reactant: CCS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CCSC(=O)[C@H](OCc1ccccc1)[C@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Yield: 15.4 %

Procedure:
Crude (R)-2-(benzyloxy)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (13 g, 46 mmol) was dissolved in CH2Cl2 (150 mL) and cooled in an ice bath. Ethanethiol (6.9 mL, 93 mmol) and N,N-dimethylpyridin-4-amine (0.11 g, 0.93 mmol) were added followed by DCC (11 g, 56 mmol). This mixture was stirred in ice bath and allowed to slowly warm to ambient temperature overnight. Acetic acid (15 mL) was added and the reaction was stirred for 10 minutes. The reaction mixture was poured into vigorously stirring ether (400 mL) and then filtered. The filtrate was washed with 10% sodium carbonate, water, 0.5 N HCl, water, brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified over silica gel (1-5% EtOAc in hexanes) to afford (R)—S-ethyl 2-(benzyloxy)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (2.3 g, 7.1 mmol, 15% yield) as a yellow oil.