Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9]([CH2:12][C:13]#[CH:14])[CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].C1(S)CCCCC1>CN(C=O)C.O>[ClH:1].[CH:25]1([S:24][C:21]2[CH:20]=[CH:19][C:18]([S:15]([C:6]3([C:4]([NH:3][OH:2])=[O:5])[CH2:7][CH2:8][N:9]([CH2:12][C:13]#[CH:14])[CH2:10][CH2:11]3)(=[O:17])=[O:16])=[CH:23][CH:22]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: SC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(SC3CCCCC3)cc2)CC1
Yield: 73 %

Procedure:
Part A: To a solution of the propargyl amine of Example 9, part F (6.5 g, 18.4 mmol) in DMF (10 mL) were added potassium carbonate (3.81 g, 27.6 mmol) and cyclohexyl mercaptan (3.37 mL, 27.6 mmol). The solution was heated to 100 degrees Celsius for 6.5 hours. The solution was diluted with H2O and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate. Chromatography (on silica, hexane/ethyl acetate) provided the sulfide as a yellow oil (6.05 g, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CCOCC.O>[CH2:34]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:7])=[CH:23][CH:24]=1)[CH2:35][CH2:36][CH3:37]
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Reactant: CCCCN(CCCC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
A mixture of 2.0 g. (6.4 mmol.) of 3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 1.3 g. (6.4 mmol.) of 3-di-n-butylaminopropyl chloride and 4.0 g. (0.04 mol.) of anhydrous potassium carbonate in 20 ml. of dry 2-butanone is refluxed for 18 hours. The reaction is cooled, water and ether are added and the layers are separated. The organic phase is extracted with 10% aqueous sodium hydroxide and the aqueous layers are combined and extracted again with water. The combined ether extracts are concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:10][CH2:9][C:8]1=[O:29])=[O:5])[CH3:2].CO>[Fe].C(O)(=O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8](=[O:29])[CH2:9][CH2:10]2)=[O:28])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc(N)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
The mixture of 1-ethoxycarbonylmethyl-5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (667 mg), iron powder (469 mg), methanol (10 ml) and acetic acid (1 ml) was refluxed for 1 hour. The reaction mixture was cooled to ambient temperature and it was filtered through a bed of celite followed by the removal of methanol. The residue was diluted with chloroform and to the mixture was added saturated sodium bicarbonate aqueous solution followed by stirring for 10 minutes. The resulting mixture was filtered through a bed of celite and the organic layer was washed with brine. Drying the filtrate, and the removal of chloroform obtained a crude product. The crude product was triturated with a mixture of diisopropyl ether and n-hexane (1:1) to give 5-(4-aminobenzoyl)-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (610 mg) as a slightly brown powder.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[F:14][C:15]([F:24])([F:25])[O:16][C:17]1[CH:18]=[C:19]([NH:20][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 3trifluoromethoxyaniline using the same procedure described in example 5.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[NH:5][C:6]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:7][C:8]=1[C:9]#[N:10].CCCCCC.C(OCC)(=O)C>O1CCOCC1>[Br:1][C:7]1[C:8]([C:9]#[N:10])=[C:4]([Cl:3])[NH:5][C:6]=1[C:11]1[S:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: N#Cc1cc(-c2ccc(Cl)s2)[nH]c1Cl
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1c(Cl)[nH]c(-c2ccc(Cl)s2)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of bromine (0.70 g, 4.3 mmol) in p-dioxane is added dropwise to a solution of 2-chloro-5-(5-chloro-2-thienyl)pyrrole-3-carbonitrile (1.00 g, 4.1 mmol) in p-dioxane. The reaction mixture is stirred overnight at room temperature and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a (6:1) hexane/ethyl acetate solution gives the title product as a yellow solid, mp >200° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH2:11]([C:18]([OH:20])=O)[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:43][C@H:44]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)[C:45]([O:47][CH3:48])=[O:46].[OH-].[Na+]>CN(C=O)C>[NH:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:18]([NH:43][C@H:44]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)[C:45]([O:47][CH3:48])=[O:46])=[O:20])[N:17]=[CH:16]1
Reactant: COC(=O)[C@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)CCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
35.5 ml of DIEA are added to a solution containing 13.2 g (74.7 mmol) of desamino-histidine hydrochloride and 24 g (74.7 mmol) of TBTU in 100 ml of DMF. After stirring for 15 minutes at ambient temperature, 14.2 g (67.9 mmol) of methyl (R)-2-amino-3-(4-methoxyphenyl)-propanoate in 150 ml of DMF are added. The reaction medium is left to stir for 16 hours and then basified to pH=8-9 by introducing 1N sodium hydroxide and a saturated solution of sodium hydrogen carbonate, followed by extraction with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated. The crude product obtained is purified by silica gel chromatography (eluent 85/15 dichloromethane/methanol). 11.0 g in the form of an orange oil are obtained with a yield of 49%.
Reaction SMILES: [C:1]([NH:4][C:5](=[S:26])[NH:6][NH:7][C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10](=[O:25])[CH:9]=1)(=[O:3])[CH3:2].ClN1C(=O)CCC1=O>CCCCCC>[C:1]([NH:4][C:5]1[S:26][C:9]2[C:10](=[O:25])[N:11]([CH2:22][CH2:23][CH3:24])[C:12](=[O:21])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[NH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCCn1c(=O)cc(NNC(=S)NC(C)=O)n(Cc2ccccc2)c1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Product: CCCn1c(=O)c2c(n(Cc3ccccc3)c1=O)NN=C(NC(C)=O)S2
Yield: 133.6 %

Procedure:
6-(4-Acetylthiosemicarbazido)-1-benzyl-3-propylpyrimidine-2,4(1H,3H)-dione (7 g) was added in portions to a mixture of N-chlorosuccinimide (3 g) at room temperature and the reaction mixture was stirred 3 further hours and then there was added hexane (200 ml). Resulting crystals were collected by filtration and washed with water to give yellowish brown crystals (9.3 g), m.p. 135°-140° C. This product was used for the subsequent reaction without further purification. In a manner analogous to the above, the following compounds (Reference Examples 7 to 10) were synthesized.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([OH:11])(=[O:10])[CH:8]=[CH2:9].O1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[CH:14]1[CH:15]=[CH:16][C:8]([C:7]([OH:11])=[O:10])=[CH:9][CH:13]=1
Reactant: C=CC(=O)O
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1

Procedure:
Following the procedure of Example 1, "Westvaco 1550 Diacid" was reduced by lithium aluminum hydride in tetrahydrofuran to a diol having formula VIII in which m is 5, p is 7 and the broken line indicates a double bond. This diol (85 grams, 0.25 mole) was reacted with acrylic acid (90 ml., 1.28 mole) in toluene solution to yield the desired diacylate as a liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][N:41]1[C:50](=[O:65])[C@H:51]([NH:63][CH3:64])[CH2:52][C:53]1[CH:62]=[CH:61][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:63]([C@H:51]([CH2:52][C:53]1[CH:62]=[CH:61][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=1)[C:50]([N:41]1[CH2:42][CH2:43][C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:65])[CH3:64])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (283 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (5.5 ml) and dichloromethane (6.5 ml). 1-Hydroxy-7-azabenzotriazole (158 mg, 1.16 mmol) was added. The mixture was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (223 mg, 1.16 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(methylamino)-3-(2-naphthyl)-1-propanone (400 mg, 1.16 mmol) in dichloromethane (4 ml) and ethyldiisopropylamine (0.2 ml, 1.16 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. I was diluted with ethyl acetate (60 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (60 ml). The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane 1:1 as eluent to give 647 mg of ((3E)-4-(N-((1R)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:10][CH2:11][CH3:12])[NH:7][C:8]=1[CH3:9])[OH:3].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O.CC(O)C>CC(C)=O>[CH2:10]([C:6]1[NH:7][C:8]([CH3:9])=[C:4]([C:2]([CH3:1])=[O:3])[N:5]=1)[CH2:11][CH3:12]
Reactant: CCCc1nc(C(C)O)c(C)[nH]1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCCc1nc(C(C)=O)c(C)[nH]1
Reaction time: 1 h

Procedure:
A suspension of 86.2 g. of α,5-dimethyl-2-n-propyl-4-imidazolemethanol in 2.16 liters of acetone is stirred in an ice bath and 430.9 ml. of Jones' reagent (120 g. of chromium trioxide, 257 ml. of water, 106.7 ml. of concentrated sulfuric acid, combined and diluted to 461.7 ml. with water) is dripped in at 20°-30° C. internal temperature over a period of one hour. Stirring is continued for 30 miuntes after the addition is complete, then 256 ml. of water were added. The reaction is then cooled in an ice bath and 256 ml. of 2-propanol are slowly added, maintaining the internal temperature at 20°-30° C. Stirring is continued for one hour, giving a suspension of solid and liquid. The liquid is decanted, concentrated to remove most of the acetone, and the aqueous residue is recombined with the solid. This mixutre is basified with concentrated aqueous potassium bicarbonate and an additional amount of solid potassium bicarbonate. The mixture is extracted with three 300 ml. portions of ethyl acetate. The extracts are combined, back washed with 100 ml. of saturated aqueous potassium bicarbonate dried over sodium sulfate and the solvent is removed in vacuo, giving the desired ketone which crystallizes on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[C:28]=4[NH:27][CH:26]=[CH:25]5)=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:29][NH:30][CH3:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[C:28]=4[NH:27][CH:26]=[CH:25]5)=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([N:30]([CH3:31])[CH3:29])=[O:5]
Reactant: Nc1ccc(-c2cnc3[nH]cc(-c4cccc5cc[nH]c45)c3c2)cc1C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(-c2cnc3[nH]cc(-c4cccc5cc[nH]c45)c3c2)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.9 %

Procedure:
To a solution of 2-amino-5-[3-(1H-indol-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (70 mg, 0.11 mmol), dimethylamine (2 N solution in THF, 0.11 mL, 0.22 mmol), diisopropylethylamine (20 mg, 0.16 mmol) in DMF (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (60 mg, 0.16 mmol). The resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with DMF (1 mL) and directly used in purification by mass-triggered reverse-phase HPLC to afford 2-amino-5-[3-(1H-indol-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a white solid (3 mg, 7%). MS: m/z 396 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 2.90 (s, 6H), 5.21 (s, 2H), 6.49 (d, 1H), 6.79 (d, 1H), 7.10 (t, 1H), 7.30 (d, 2H), 7.33 (d, 1H), 7.43 (dd, 1H), 7.49 (d, 1H), 7.81 (d, 1H), 8.03 (d, 1H), 8.44 (m, 2H), 10.89 (s, 1H), 11.99 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([S:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:25]OS([O-])=O.[K+].S(OOS([O-])(=O)=O)([O-])(=O)=O>CC(C)=O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([S:18]([CH2:19][C:20]([OH:22])=[O:21])=[O:25])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(O)CSC1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)CS(=O)C1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of optically resolved tR2 (AS, 300 mg) of ({1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid obtained in Example 11 in acetone (10 mL) was added aqueous solution (5 mL) of Oxone-persulfate compound (500 mg) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The acetone was evaporated under reduced pressure, and the precipitate was collected by filtration. The precipitate was washed with water and hexane to give the title compound (311 mg, yield 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18]C=[C:16]3[C:11]=2C=CC=[N:15]3)=[CH:4][CH:3]=1.[CH:25]1[C:37]2[CH:36]([C:38](O)=[O:39])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:21]([N:20]=[C:8]([NH:9][C:10]1[CH:11]=[CH:16][N:15]=[CH:18][CH:19]=1)[NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:38]([CH:36]2[C:37]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:39])=[CH:24][CH:23]=1)#[N:22]
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CN=C(NCc1ccc(NC(=O)C2c3ccccc3-c3ccccc32)cc1)Nc1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (133 mg, 0.50 mmol) and 9H-fluorene-9-carboxylic acid (105 mg, 0.50 mmol) were suspended in N,N-dimethylformamide(1.0 mL). Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (232 mg, 0.52 mmol) was added followed by N,N-diisopropylethylamine (0.20 mL, 1.15 mmol). The reaction mixture was stirred at room temperature for 24 hours and then diluted with ethyl acetate (30 mL). This solution was washed with water (30 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the desired product (102 mg, 44.5%). 1H NMR (DMSO-d6, ppm): 10.72 (s, 1H), 9.59 (bs, 1H), 8.37 (d, 2H), 8.27 (bs, 1H), 7.90 (d, 2H), 7.60 (t, 4H), 7.43 (t, 2H), 7.31 (m, 4H), 7.18 (m, 2H), 5.03 (s, 1H), 4.43 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][NH:17][C:11]=3[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[CH:4][CH:3]=1.[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:31]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:32])[C:11]=3[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[CH:6][CH:7]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=c1c2cn[nH]c2nc(-c2ccccc2F)n1-c1ccc(Br)cc1
Solvent: c1ccncc1
Product: O=C(N1CCOCC1)n1ncc2c(=O)n(-c3ccc(Br)cc3)c(-c3ccccc3F)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of 5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (20.0 mg, 0.052 mmol) in anhydrous pyridine (0.5 mL) is added 4-morpholinecarbonyl chloride (7.27 μL, 0.062 mmol). The mixture is stirred at room temperature for 2 h before removal of the solvent. The residue is purified by preparative LCMS followed by preparative TLC to provide the title compound (9.1 mg, 35% yield) as a white solid product; 1H NMR (CDCl3, 400 MHz) δ 8.91 (s, 1H), 7.42-7.28 (m, 4H), 7.11 (t, 1H), 7.02 (d, 2H), 6.88 (t, 1H), 4.15-3.84 (m, 8H); HPLC-MS calculated for C22H17BrFN5O3 (M+H+) 498.0. Found: 498.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25](Cl)[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:23]3Cl)([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH3:38][N:39](C)C(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:9])([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=2)[C:20]2[CH:29]=[C:28]3[C:27](=[CH:22][CH:21]=2)[N:26]=[C:25]([C:38]#[N:39])[C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:23]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: OC(c1ccc(C(F)(F)F)nc1)(c1cccc(Cl)c1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cccc(Cl)c3)cc2cc1-c1ccccc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A pressure tube containing (3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (94 mg, 0.17 mmol, Intermediate 22: step b), Pd2(dba)3 (8.0 mg, 0.0087 mmol), 1,1′-bis(diphenylphosphino)ferrocene (dppf, 10 mg, 0.018 mmol), zinc cyanide (25 mg, 0.21 mmol), and zinc nanopowder (3.0 mg, 0.046 mmol) in N,N-dimethylacetamide (1 mL) was sparged with nitrogen for 5 minutes, and then heated at 120° C. for 1 hour followed by 100° C. for 3 hours. The mixture was allowed to cool to room temperature and filtered through a syringe filter. The filtrate was concentrated in vacuo, then EtOAc and NH4OH (aqueous) were added. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel column, 30-50% EtOAc in heptane), and then by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a by-product. 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=2.02 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J=9.60 Hz, 1H), 7.93 (dd, J=2.02, 8.08 Hz, 1H), 7.75-7.79 (m, 2H), 7.71 (d, J=8.08 Hz 1H), 7.60-7.65 (m, 2H), 7.51-7.58 (m, 3H), 7.32-7.40 (m, 3H), 7.15 (dt, J=1.52, 7.58 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([NH2:19])[CH:10]=1)(C)(C)C.Cl>C1COCC1>[NH2:19][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[C:15]([F:16])([F:17])[F:18])[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(F)(F)F)c(N)c1
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ccc(C(F)(F)F)c(N)c1
Yield: 99 %

Procedure:
The title compound was prepared from tert.-butyl-N-(3-amino-4-trifluoromethyl-benzyl)carbamate and—6M HCl in THF in analogy to example 2e.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:14][Cl:15])(=O)=O)=CC=1.[I-:24].[Na+]>CC(C)=O>[C:20]([Si:17]([O:16][CH:13]([CH2:12][I:24])[CH2:14][Cl:15])([CH3:19])[CH3:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCC(CCl)O[Si](C)(C)C(C)(C)C)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCl)CI
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a mixture of 2-{[tert-butyl(dimethyl)silyl]oxy}-3-chloropropyl 4-methylbenzenesulfonate (20.3 g) in acetone (200 mL) was added sodium iodide (19.7 g), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with hexane. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.4 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CCOCC>N1C=CC=CC=1>[CH3:17][C:16]1[CH:18]=[CH:19][C:13]([S:10]([O:8][CH2:7][C@@H:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol LIV (23.1 g, 0.175 mol) in pyridine (150 mL) at 0° C. was added tosyl chloride (44.5 g, 0.23 mol) in portions. The mixture was stirred for 7 h at 0° C. and was placed in a refrigerator for 18 h. Et2O (150 mL) was added and the mixture was washed with 1 N aqueous HCl (5×150 mL). The organic layer was washed with aqueous NaHCO3 (150 mL) and water (150 mL). The organic phase was dried over Na2SO4, filtered, concentrated and dried under vacuum. The crude product was purified by column chromatography on silica gel (1:1 Et2O:hexane) to afford (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate LV (42.1 g, 0.15 mol, 84%).