Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:32])=[C:6]([CH:10]=[C:11]([CH:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:16][C:15](=[O:31])[NH:14]2)[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].[NH4+].[Cl-].CC[N:37]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:5]([OH:32])=[C:6]([CH:10]=[C:11]([CH:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:16][C:15](=[O:31])[NH:14]2)[CH:12]=1)[C:7]([NH2:37])=[O:9])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(C(=O)O)c1O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(C(N)=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A mixture of Compound 77 (described previously) (280 mg, 0.65 mmol), NH4Cl (41 mg, 0.78 mmol), EDCI (149 mg, 0.78 mmol), HOBT (105 mg, 0.78 mmol), and NMM (0.29 mL, 2.6 mmol) in DMF (5 mL) was stirred at room temperature for two hours. LCMS showed most of the starting material was consumed. 100 mL of a mixture of EtOAc and MeOH (v/v=10:1) was added to dilute the mixture. The organic layer was washed with brine (20 mL×2), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to afford Compound 82 as a yellow solid (46 mg, yield: 16.4%). 1H NMR (DMSO-d6 400 MHz): δ 12.94 (s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 7.37 (s, 1H), 7.33 (s, 1H), 7.20-7.25 (m, 5H), 7.11 (s, 1H), 6.97-7.02 (m, 3H), 6.80 (d, J=6.8 Hz, 2H), 5.10 (d, J=2.4 Hz, 1H), 4.00 (q, J=7.2 Hz, 2H), 1.32 (t, J=6.8 Hz, 3H); MS (ESI): m/z 430.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]=[C:38]=[O:39]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[NH:37][C:38]([NH:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8])=[O:39]
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.5 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 2-chloro-1-isocyanato-4-(trifluoromethyl)benzene (62 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (125 mg, 64%) as a colorless powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([F:18])[CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[C:19](=[O:22])([O-])[O-].[K+].[K+]>N1CCOCC1.C(Cl)Cl>[F:18][C:13]1[CH:12]=[C:11]([C:8]2[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][N:9]=2)[CH:16]=[CH:15][C:14]=1[N:4]1[CH2:5][CH2:19][O:22][CH2:2][CH2:1]1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NCC1CC(c2ccc(F)c(F)c2)=NO1
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC(=O)NCC1CC(c2ccc(N3CCOCC3)c(F)c2)=NO1
Temperature: 140 °C

Procedure:
To a resealable tube containing (+/-)-N-[[4,5-dihydro-3-(3,4-difluorophenyl)-5-isoxazolyl]methyl]acetamide (Step 3, Example 3) (1.70 g) in morpholine (5.83 mL) is added potassium carbonate (1.16 g) and heated to 140° C. for 48 hours. The reaction is diluted with CH2Cl2 (50 mL) and washed with H2O (3×50 mL) and saline (50 mL). The organic phase is dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh), eluting with methylene chloride/methanol (98.5/1.5). The appropriate fractions are combined (Rf =0.30, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound. The racemic material is separated on chiral HPLC (Chiralpak AD column, eluting with 8:2:1.5 heptane/isopropanol/chloroform) to give the individual enantiomers, the title compound having mp 179-180° C., [α]25D -71° (DMSO).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]2)=[CH:3][CH:2]=1.[CH3:21][O:22][C@:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:27]([F:30])([F:29])[F:28])[C:24](O)=[O:25].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:24](=[O:25])[C@@:23]([O:22][CH3:21])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:27]([F:29])([F:30])[F:28])[CH2:9]2)=[CH:3][CH:2]=1
Reactant: CO[C@](C(=O)O)(c1ccccc1)C(F)(F)F
Reactant: O[C@@H]1CCC[C@H](Oc2ccc(-c3ccccc3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@](C(=O)O[C@@H]1CCC[C@H](Oc2ccc(-c3ccccc3)cc2)C1)(c1ccccc1)C(F)(F)F
Temperature: 36 °C

Procedure:
A mixture of (1R*,3S*)-3-(Biphenyl-4-yloxy)-cyclohexanol from Step C (1 eq) with (S)-(−)-α-methoxy-α-(trifluoromethyl)-phenylacetic acid (1 eq), DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was stirred at 36° C. over night. The reaction mixture was cooled and concentrated to dryness. Reconstituted in: ether and washed with HCl 1N, and NaHCO3. Dry over MsSO4 and concentrated in vacuo to give a crude that was purified by silica gel chromatography to give a diastereomeric mixture which was separated using chiral HPLC
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:12]([CH2:21][CH3:22])=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:21]([C:12]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[CH:14][C:9]([OH:8])=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:11]=1)[CH3:22]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCN
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCCN
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
A flask was charged with 10% palladium on carbon (200 mg), ethanol (20 mL), and 1-benzyloxy-2-(4-fluorophenyl)-4-ethyl-5-[(4-aminobutyl)oxy]-benzene (500 mg). The flask was fitted with a balloon and pressurized with hydrogen to fully inflate the balloon. The reaction was stirred 3.5 hours, filtered through Celite, and the filtrate concentrated under vacuum to afford 4-ethyl-2-(4-fluorophenyl)-5-[(4-aminobutyl)oxy]phenol as a white powder (350 mg). HPLC showed that ˜25% starting material remained. It was not purified but carried directly into the next step. Mass Spec (EI), m/e=304.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][O:28][CH2:29][C@@H:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:32][C@@H:30]([CH3:31])[CH2:29][O:28][CH3:27])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: COC[C@H](C)N
Product: COC[C@H](C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (S)-1-methoxy-2-propylamine via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-methoxypropan-2-yl)terephthalamide. MS (Q1) 459 (M)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: Ic1c[nH]c2ncccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
3-Iodo-1H-pyrrolo[2,3-b]pyridine 634 (2.00 g, 8.20 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (60% dispersion in mineral oil, 390 mg, 9.8 mmol) was added. After 20 minutes, triisopropylsilyl chloride (1.74 mL, 8.20 mmol) was added dropwise. After 1.5 hours, the reaction was poured into water and extracted with ethyl acetate, washed with saturated sodium bicarbonate and brine. The organic portions were dried over anhydrous sodium sulfate and concentrated. Purification by silica gel chromatography, 0-25% gradient ethyl acetate/hexane gave compound 635 as a white solid (3.224 g, 98.2%). 1H-NMR was consistent with the desired compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][N:1]([CH2:32][CH:29]2[CH2:31][CH2:30]2)[CH2:2][CH2:3][NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=4[O:17][B:16]3[OH:28])=[O:13])[CH2:7][CH2:6]2)[CH2:31][CH2:30]1
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: O=CC1CC1
Product: O=C(C[C@H]1CC[C@H](NCCN(CC2CC2)CC2CC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid and cyclopropanecarbaldehyde following the procedure described in Example 71. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 498 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([S:25][CH2:26][CH3:27])=[CH:4][CH2:3]1.[CH3:29][C:30]1(C)C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2C(=O)[CH2:32][CH2:31]1>>[CH3:28][C:2]1([CH3:1])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:27]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(SCC)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(Sc2ccccc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151), 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5,5-dimethyl-8-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (colorless flakes, recrystallized from hexane) using 0.268 g (1.42 mmol) of titanium tetrachloride, 172 mg (1.56 mmol) of thiophenol and 291 mg (2.88 mmol) of triethylamine.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=1)([O-:5])=[O:4]
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 86.9 %

Procedure:
To a solution of 10.38 gm (185 mMol) potassium hydroxide in 200 mL methanol were added 10.0 gm (61.7 mMol) 5-nitro-1H-indole followed by 13.96 gm (123 mMol) 1-methyl-4-piperidone. The mixture was heated to reflux for 4 days under a nitrogen atmosphere. The reaction mixture was then allowed to cool to ambient and the solid which formed filtered and washed with methanol This solid was dried under vacuum at 50° C. The combined filtrates were then concentrated under reduced pressure and the residue subjected to flash chromatography, eluting with 92.5:7.5 dichloromethane:methanol. Fractions shown to contain product were combined and concentrated under reduced pressure. This solid was combined with that isolated directly from the reaction mixture to give 13.79 gm (87%) 5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: O[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C[OH:13]>[Pt]=O>[OH:13][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH2:2][CH3:11]
Reactant: CC(O)C(=O)c1ccccc1
Reactant: CO
Agent: O=[Pt]
Product: CCC(O)c1ccccc1O
Reaction time: 1 h

Procedure:
A mixture of platinum oxide (302 mg) in methanol (30 mL) is stirred under a hydrogen atmosphere (balloon) for 1 hr and then treated with 2-hydroxypropiophenone (2.00 g). The mixture is stirred under hydrogen for 4 hrs, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give an oily residue which is chromatographed on silica gel (230-400 mesh, 200 ), eluting with a gradient of ethyl acetate/hexane (5/95-20/80). Pooling of fractions with an Rf =0.41 by TLC (ethyl acetate/hexane, 25/75) and removal of solvent under reduced pressure gives the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>O1CCOCC1>[C:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1/[N:12]=[CH:15]/[N:16]([CH3:18])[CH3:17])#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)/C=N/c1ccc([N+](=O)[O-])cc1C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 5-nitroanthranilonitrile (1.00 g, 6.13 mmol) in dioxane (25 mL) was added dimethylformamide dimethylacetal (0.88 g, 7.36 mmol). The reaction mixture was stirred at 100° C. for 2 h and then cooled to room temperature and refrigerated. The precipitate was filtered out, washed with cold ether several times, and then dried in vacuo to give 1.30 g (97%) of (E)-N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(N(CC)CC)C>[Br:8][C:4]1[N:3]=[C:2]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCCC
Reactant: Brc1cccc(Br)n1
Solvent: CCN(CC)CC
Product: CCCCC#Cc1cccc(Br)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2,6-Dibromopyridine (2.36 g, 10 mmole) is suspended in 32 ml degassed triethylamine in a 100 ml one-neck round bottom flask under argon. The suspension is treated successively with (bis)triphenylphosphine palladium dichloride (62 mg, 0.08 mmole) and cuprous iodide (8 mg, 0.04 mmole) and is warmed to 50° C. 1-Hexyne (0.50 ml, 4.4 mmole), in 4 ml triethylamine, is added slowly dropwise to the reaction mixture over 30 minutes at 50° C. The reaction is stirred an additional one hour at 50° C., cooled to room temperature, and the triethylamine hydrobromide is removed by filtration. The filtrate is concentrated in vacuo to a white pasty solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=O)[O:11][C:12](=[O:14])[CH:13]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(CC#[N:28])=CC=1.O.C(O)(=O)C=O.C(=O)([O-])[O-].[K+:41].[K+]>CO>[K+:41].[C:10]([C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=1)=[CH:13][C:12]([O-:11])=[O:14])#[N:28]
Reactant: O=C1C=C(c2ccc(C(F)(F)F)cc2)C(=O)O1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: O=CC(=O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC(=CC(=O)[O-])c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(4-Trifluoromethyl-phenyl)-furan-2,5-dione. A mixture of 4-(trifluoromethyl)phenylacetonitrile (9.26 g, 50 mmol), glyoxylic acid monohydrate (6.9 g, 75 mmol), and potassium carbonate (17 g, 125 mmol) in methanol (100 mL) was stirred at room temperature for 3-5 h. The resulting thick solid precipitate was filtered and washed with dichloromethane. This solid was suspended in 250 mL of water, stirred overnight, and filtered and air-dried to provide 3-cyano-3-(4-trifluoromethyl-phenyl)-acrylic acid potassium salt. This was dissolved in 88% formic acid (ca. 200 mL) containing concentrated sulfuric acid (15 mL). This mixture was heated at reflux for 2-3 h and cooled and poured into ice water. The resulting precipitate was collected by filtration, washed with water, and air dried to provide the title compound. 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 7.97 (d, J=8.2 Hz, 2H), 8.24 (d, J=8.2 Hz, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:20]3[NH:27][CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]>CN(C)C=O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:20]3[N:27]([S:44]([C:38]4[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:36]([O:35][CH3:34])[CH:37]=4)(=[O:46])=[O:45])[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4cc[nH]c34)cc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1OC
Reaction time: 1 h
Yield: 45.1 %

Procedure:
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride (150 mg) was dissolved in N,N-dimethylformamide (1.5 mL), and potassium carbonate (102 mg) and (3,4-dimethoxyphenyl)sulfonyl chloride (96.9 mg) were sequentially added under ice-cooling. The mixture was stirred under ice-cooling for 2 hrs, and at room temperature for 1 hr. The mixture was diluted with ethyl acetate (50 mL) and washed twice with water (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (95 mg) as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:17])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: Fc1cc(CBr)ccc1Br
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3-fluorotoluene (39.4 g, 0.21 mol), NBS (38.1 g, 0.22 mol) and AIBN (5 g, 0.03 mol) in 250 mL CH2Cl2 was heated at reflux for 6 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was washed with water, brine, and concentrated under vacuum to afford 1-bromo-4-(bromomethyl)-2-fluorobenzene, which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:33]([CH2:34][CH3:35])[C:26]5=[CH:27][N:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:33]([CH2:34][CH3:35])[C:26]5=[CH:27][N:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2cc(OC)ncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2cc(OC)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of (R)-tert-butyl(1-(2-(1-ethyl-5-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (106 mg, 0.199 mmol) in dichloromethane (DCM) (3 mL) was added TFA (3 mL, 38.9 mmol) dropwise with continuous stirring. The reaction was stirred at room temperature under nitrogen for 1 hr. LCMS showed the reaction was complete with no starting material remaining. The reaction mixture was concentrated in vacuo before being dissolved in MeOH and purified by SPE on sulfonic acid (SCX) 5 g, first washing with MeOH and then eluting using a 10% NH3/MeOH solution to give the free base of the product. The appropriate fractions were combined and evaporated in vacuo before being azeotroped with cHex and dried on the high vacuum line to give the required product (69 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([OH:15])[CH2:13][OH:14])[CH:8]=[CH:7]2.CO[C:18](OC)([CH3:20])[CH3:19].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]1[CH2:13][O:14][C:18]([CH3:20])([CH3:19])[O:15]1)[CH:8]=[CH:7]2
Reactant: OCC(O)c1ccc2cccc(Br)c2n1
Reactant: COC(C)(C)OC
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccc3cccc(Br)c3n2)O1
Reaction time: 2 h

Procedure:
To 1-(8-bromoquinolin-2-yl)ethane-1,2-diol (505 mg, 1.88 mmol) in acetone (5 mL) and 2,2-dimethoxypropane (5 mL, 1.88 mmol) was added Montmorillonite K 10 (1 g). The reaction mixture was stirred for 2 hours, then filtered and concentrated to give crude product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][NH:67][C:68]([CH3:72])([CH3:71])[CH2:69][CH3:70])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][NH:67][C:68]([CH3:72])([CH3:71])[CH2:69][CH3:70])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: CCC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: CCC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-[2-(1,1-dimethyl-propylamino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=563, obsd.=563).