Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.Cl.[F:29][CH2:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([N:32]4[CH2:33][CH2:34][CH2:35][C@H:31]4[CH2:30][F:29])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: FC[C@@H]1CCCN1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 382.2 mg, 0.86 mmol), (S)-2-(fluoromethyl)pyrrolidine hydrochloride (240 mg, 1.72 mmol), potassium fluoride (250 mg, 4.30 mmol), DMSO (2.6 mL), and N,N-diisopropylethylamine (0.75 mL, 4.30 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C25H28ClFN6 [M+H]+ 467. found 467.
Reaction SMILES: ClC1C=CC([C@@H:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][C:12]=2F)C)=CC=1.C([C:22]1[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[C:24]([CH2:31][CH3:32])[C:23]=1N)C>>[CH2:31]([C:24]1[CH:23]=[CH:22][C:27]([NH:28][CH2:13][C:14]2[CH:8]=[N:10][C:11]([CH3:12])=[CH:16][CH:15]=2)=[CH:26][CH:25]=1)[CH3:32]
Reactant: COc1ccc(N[C@@H](C)c2ccc(Cl)cc2)c(F)c1
Reactant: CCc1ccc([N+](=O)[O-])c(CC)c1N
Product: CCc1ccc(NCc2ccc(C)nc2)cc1
Yield: 48 %

Procedure:
292 μl (2.085 mmol; 5 eq.) of (S)-4-chlora-alpha-methylbenzylamine (3) react according to GP-1B with 76 mg (0.417 mmol; 1.0 eq.) of 2-hydroxymethyl-4-methoxybenzyl-boronic acid (2). Flash chromatographical purification (hexane/ethylacetate 10:1) yields 58.6 mg (0.2 mmol; 48%) of the desired amine 4.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]([OH:11])=[O:10])=[CH:3]1.[C:12](Cl)(=O)C(Cl)=O>ClCCl>[CH3:12][O:10][C:9]([C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:11]
Reactant: Cn1cc(C(=O)O)ccc1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(=O)n(C)c1
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
The mixture obtained in Example 26 (˜2.5 g total) was dissolved in dichloromethane (30 mL). Oxalyl chloride (2 M in dichloromethane, 16.3 mL. 32.6 mmol) was added and the reaction was stirred for 30 min. The reaction was quenched with methanol, then diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated, then chromatographed in 20-50% ethyl acetate in hexanes to yield the title product 1.55 g, 26% (2 steps).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:13][C:14](=[O:16])[CH3:15].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:13][C:14](=[O:16])[CH3:15]
Reactant: [H][H]
Reactant: COCCC#Cc1ccncc1OC(C)=O
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: COCCCCc1ccncc1OC(C)=O

Procedure:
To a degassed solution of 9.9 mmol acetic acid 4-(4-methoxy-but-1-ynyl)-pyridin-3-yl ester and 0.51 mmol quinoline in 230 ml ethyl acetate is added 0.56 mmol 10% Pd/C. The suspension is vigorously stirred under an atmospheric pressure of hydrogen for 2 hours. The catalyst is removed by filtration and the solvent is evaporated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and identified based on its Rf value.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=C(N)C=2)=[CH:4][C:3]=1Br.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Sc2cc(Br)c(N)c3c2C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Example 15 was repeated, except that the compounds described in 1st, 2nd and 3rd columns of the following table were used in place of the 1-amino-2-bromo-4-(3'amino-4'-sulfophenylthio)anthraquinone, 1-aminobenzene-4-β-sulfatoethylsulfone and 3-aminobenzenesulfonic acid, respectively, thereby obtaining a corresponding anthraquinone compound. The color shade obtained by dyeing cotton with the compound is as shown in a 4th column of the table.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccc(C(N)=O)s1
Product: Cc1ccc(-c2nc(CCl)co2)s1
Yield: 46 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-methyl-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole. The yield was 46%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 84-85° C.
Reaction SMILES: [C:1]1([CH:7]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]2[CH2:13][NH:12][C:11](=O)[CH2:10][O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[C:1]1([C@H:7]([O:15][C:16]2[C:17]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[C@H:8]2[O:9][CH2:10][CH2:11][NH:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1COC(C(Oc2cccnc2)c2ccccc2)CN1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ncccc2O[C@@H](c2ccccc2)[C@@H]2CNCCO2)cc1

Procedure:
(S)-2-[(S)-Phenyl-(2-p-tolyl-pyridin-3-yloxy)-methyl]-morpholine was synthesized from the corresponding amide (6-[Phenyl-(pyridin-3-yloxy)-methyl]-morpholin-3-one) using General Procedure B (employing 4-methylphenylboronic acid in the coupling step) and gave 0.20 g of light brown oil. Two chromatographies of the reaction product on silica gel (eluent—3:1 ethyl acetate/methanol) gave 0.080 g (35%) of the desired product. 1H NMR (400 MHz, CDCl3) δ8.24 (m, 1H), 7.96 (d, 2H), 7.27 (m, 7H), 7.07 (m, 1H), 6.98 (m, 1H), 5.13 (d, 1H), 3.96 (m, 1H), 3.87 (m, 1H), 3.64 (m, 1H), 2.80 (m, 2H), 2.53 (m, 2H), 2.44 (s, 3H). (MS) m/z 361.07 [C23H24N2O2+H+].
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:30](=[CH:31][CH:32]=2)[O:29][C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][C:21]3=[O:33])[CH:15]=[N:14]1.[CH:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[C:44]([C:47](O)=[O:48])[CH:43]=[C:42]3[OH:50])[CH2:36][CH2:35]1.O>CN(C=O)C>[CH:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[C:44]([C:47]([N:26]2[CH2:25][CH2:24][C:23]4([CH2:22][C:21](=[O:33])[C:20]5[C:30](=[CH:31][CH:32]=[C:18]([C:16]6[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=6)[CH:19]=5)[O:29]4)[CH2:28][CH2:27]2)=[O:48])[CH:43]=[C:42]3[OH:50])[CH2:35][CH2:36]1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Reactant: O=C(O)c1cc(O)c2cccc(C3CC3)c2n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(O)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (0.657 ml, 4.71 mmol) was added to a stirred mixture of HOBT (313 mg, 2.04 mmol), WSCDI (361 mg, 1.89 mmol), 6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (629 mg, 1.89 mmol) and 8-cyclopropyl-4-hydroxyquinoline-2-carboxylic acid (360 mg, 1.57 mmol) in DMF (3.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (20 ml) and stirred for 30 min. The resulted precipitate was filtered, washed with water and the solid was dried in vacuo at 70° C. The crude product was purified by silicagel column chromatography (CHCl3/AcOEt) to give intended compound as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:15]([CH3:16])=[CH:14][CH:10]=[C:11]1[CH3:13]
Reactant: Nc1ccc(I)cc1F
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(I)cc1F
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 2-fluoro-4-iodoaniline (25.3 g, 107 mmol), acetonylacetone (14.9 g, 131 mmol) and para-toluenesulfonic acid (203 mg, 1 mmol) in dry toluene was heated under reflux for 1 h with a Dean-Stark tap. After cooling to room temperature the mixture was poured into sodium hydrogen carbonate (saturated). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and then boiled with charcoal. Filtering to remove the charcoal followed by evaporation afforded the title compound (33.2 g, 98%) as a light brown solid. MS: m/e=315.1 (M++H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)OC)#[N:2].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=[N:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: COC(=NC#N)c1ccoc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1ccoc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Methyl N-cyano-3-furancarboximidate (0.30 g, 2.0 mmol) was dissolved in methanol (10 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.38 g, 1.59 mmol, yield: 79%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[Cl:9][C:10]1=[C:11](Cl)[C:12](O[C:15]1=O)=O.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C=CC(Cl)=C.Cl>O>[Cl:9][C:10]1[CH2:15][C:7]2[C:6](=[O:8])[O:5][C:3](=[O:4])[C:2]=2[CH2:12][CH:11]=1
Reactant: O=C1C=C(Cl)C(=O)O1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Agent: C=CC(=C)Cl
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Product: O=C1OC(=O)C2=C1CC=C(Cl)C2
Temperature: 105 °C

Procedure:
A 3-necked 50 mL flask was equipped with a pressure equalizing addition funnel, a thermocouple well with thermocouple, a water cooled condensor and a magnetic stir bar. The flask was charged with 13.2 g (0.10 mol) of a 90/10 GC area % mixture of monochloromaleic anhydride and dichloromaleic anhydride and 50 mg of phenothiazine. The contents of the flask were heated to 80 to 130° C. and 8.8 g (0.1 mol) of chloroprene was added over 15 to 30 minutes. HCl gas was observed evolving from the reactor. After 6 hours at 130° C. the contents of the flask were multiple distilled into two fractions resulting in the isolation of 12.08 g of 4-chloro-3,6-dihydrophthalic anhydride which was identified by 13C 1H NMR and MS.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([CH3:27])=[CH:11][C:12]([O:15][CH2:16][C:17]3[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[F:14][C:13]1[C:8]2[S:7][CH:6]=[C:5]([CH2:4][C:3]([OH:28])=[O:2])[C:9]=2[C:10]([CH3:27])=[CH:11][C:12]=1[O:15][CH2:16][C:17]1[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: COC(=O)Cc1csc2c(F)c(OCc3cc(C(F)(F)F)nn3C)cc(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2cc(C(F)(F)F)nn2C)c(F)c2scc(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a mixture of methyl(7-fluoro-4-methyl-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (150.6 mg), THF (dry) (2.0 mL) and MeOH (2.0 mL) was added 1N NaOH (1.085 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl and concentrated. The precipitate was collected by filtration to give a solid. The solid was crystallized from EtOAc-hexane to give the title compound (123.5 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1.F[C:22]1C=CC(C(C2C=CC(OCCO)=CC=2)=O)=C[CH:23]=1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)([OH:12])[C:22]#[CH:23])=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)c2ccc(OCCO)cc2)cc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(OCCO)cc1
Product: C#CC(O)(c1ccc(OC)cc1)c1ccc(OCCO)cc1

Procedure:
The procedure of Step 1 of Example 5 of U.S. Pat. No. 7,465,415B2 was followed except that the product of Step 5 above was used in place of (4-fluorophenyl)(4-(2-hydroxyethoxy)phenyl)methanone to produce 1-(4-(2-hydroxyethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-yn-1-ol. The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:9][C@@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1ccccc1

Procedure:
Following a procedure similar to that described in Example (59b), 3.90 g of N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]-N-[(R)-1phenylethyl]amine [prepared as described in step (a) above], 5.29 g of nickel chloride hexahydrate and 1.68 g of sodium borohydride were reacted, separated and purified, to obtain 1.24 g of isomer A and 848 mg of isomer B of the title compound, each as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.[C:24]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>ClCCl>[C:27]([O:26][C:24](=[O:25])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=2[CH:7]=1)=[O:12])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(Br)ccc2o1
Yield: 72.4 %

Procedure:
A mixture of 5290 mg (21.95 mmol) 5-Bromo-benzofuran-2-carboxylic acid (Owen, C. P., et al., J. Pharm. Pharmacol. 51 (1999) 427–434) and 20 ml thionyl chloride was heated at reflux for 4 h. The excess thionyl chloride was evaporated, 20 ml toluene were added and evaporated again. The residue was dissolved in 50 ml dichloromethane and 2.0 ml pyridine and a solution of 4373 mg (21.0 mmol) mono-boc-orthophenylenediamine in 30 ml dichloromethane were added at 0° C. After 12 h the precipitate was filtered off and washed with diethyl ether to give a first crop of 6550 mg (15.2 mmol) {2-[(5-Bromo-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (56). The solvent of the mother liquid was removed and 250 ml ethyl acetate were added to the residue. The organic phase was washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate solution and brine and dried over Na2SO4. 50 ml heptane were added to the solution and the solvent was evaporated to give another 1000 mg of (2.32 mmol) of {2-[(5-Bromo-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (56).
Reaction SMILES: [CH:1]1([O:5][C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Ca+2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20].C(Cl)Cl.CO>C1(C)C=CC=CC=1>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[NH:12][C:9]2[CH:10]=[N:11][C:6]([O:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[CH:7][CH:8]=2)=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: Nc1ccc(OC2CCC2)nc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc(OC2CCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
A mixture of 6-cyclobutoxy-pyridin-3-ylamine (4.41 g, assume 25 mmol), as prepared in the previous step, and CaCO3 (3.25 g, 32.5 mmol) (10 micron powder) was treated with a homogeneous solution of 4-nitrophenyl chloroformate (5.54 g, 27.5 mmol) in toluene (28 mL) in one portion at rt, and was stirred at “rt” (reaction warmed spontaneously) for 2 h. The reaction mixture was then directly loaded onto a flash silica column (95:5 DCM/MeOH→9:1 DCM/MeOH) to afford 5.65 g of material, which was further purified by trituration with hot toluene (1×200 mL) to provide the title compound (4.45 g, 54%). 1H NMR (400 MHz, CDCl3) δ 8.28 (m, 2H), 8.12 (d, 1H), 7.81 (m, 1H), 7.39 (m, 2H), 6.85 (br s, 1H), 6.72 (d, 1H), 5.14 (m, 1H), 2.45 (m, 2H), 2.13 (m, 2H), 1.84 (m, 1H), 1.68 (m, 1H). LC-MS (ESI): calcd mass 329.1, found 330.1 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][C:13]=2[CH3:22])[N:3]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.FC(F)(F)C(O)=O>FC(F)(F)CO>[CH:19]1([C:15]2[CH:16]=[C:17]([CH3:18])[C:12]([O:11][C:4]3[N:3]=[C:2]([NH:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[N:10]=[C:9]4[C:5]=3[N:6]=[CH:7][NH:8]4)=[C:13]([CH3:22])[CH:14]=2)[CH2:21][CH2:20]1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]cnc12
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2[nH]cnc12
Temperature: 90 °C
Yield: 20.1 %

Procedure:
To a suspension of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine (28 mg, 0.088 mmol) and 4-aminobenzonitrile (42 mg, 0.35 mmol) in 2,2,2-trifluoroethanol (3 mL) in a sealed tube was added trifluoroacetic acid (0.056 mL, 0.70 mmol). The resulting solution was heated at 90° C. for 3 days. The reaction was cooled to room temperature and concentrated to dryness. Silica gel chromatography (CH2Cl2:Acetone=80:20) yielded 7 mg (20%) of 4-(6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purin-2-ylamino)benzonitrile as a light yellow solid.
Reaction SMILES: [CH:1]([NH:3]/[C:4](/[C:14](/[NH:24][CH:25]=O)=[CH:15]\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=O.ClCCl.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[N+:3](/[C:4](/[C:14](/[N+:24]#[C-:25])=[CH:15]\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])#[C-:1]
Reactant: COc1ccccc1/C=C(NC=O)\C(=C/c1ccccc1OC)NC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C(=C/c1ccccc1OC)/C(=C\c1ccccc1OC)[N+]#[C-]
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
1,1′-[(1E,3E)-2,3-diformylamino-1,3-butadiene-1,4-diyl]bis[methoxybenzene] (3.4 mg, 0.0096 mmol) prepared in Reference Synthetic Example 6 was suspended in chloroform (100 μl) and pyridine (100 μl), and a dichloromethane solution of phosphorus oxychloride (2 μl, 0.021 mmol) was dropwise added under cooling with ice. After stirring for 30 minutes, the suspension was diluted with ethyl acetate and poured into a saturated sodium hydrogen carbonate aqueous solution. Extraction with ethyl acetate was carried out twice, and the obtained organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired compound 1,1′-[(1E,3E)-2,3-diisocyano-1,3-butadiene-1,4-diyl]bis[methoxybenzene] (2.2 mg, 72%) as liver brown solid.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1>CCOCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12](=[O:14])[CH3:1])=[CH:8][CH:9]=1
Reactant: [Li]C
Reactant: O=C(O)CCc1ccc(Cl)cc1
Solvent: CCOCC
Product: CC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.6 M Methyl lithium (33.9 mL, 54.17 mmol) was added over 70 min to a stirring 0° C. solution of 3-(4-chlorophenyl)-propionic acid (5.0072 g, 27.08 mmol) in dry Et2O (135 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature overnight. The reaction was the poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 98:2 to 95:5 Hexanes: EtOAc) to achieve pure 66 (2.4253 g, 49.0%): 1H (CDCl3, 400 MHz): δ 7.14 (2H, d, J=8.3 Hz), 7.03 (2H, d, J=8.3 Hz), 2.77 (2H, t, J=7.5 Hz), 2.64 (2H, t, J=7.5 Hz), 2.04 (3H, s) ppm. 13C (CDCl3, 100 MHz): δ 207.12, 139.38, 131.59, 129.55, 128.35, 44.62, 29.82, 28.78 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 29.82; CH2 carbons: 44.62, 28.78; CH carbons: 129.55, 128.35 ppm. HPLC: 10.361 min. (Note: SM has HPLC retention time of 9.409 min.)
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[CH3:19][Mg]Br>C1COCC1>[C:4]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1)(=[O:5])[CH3:19]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate in THF (18 mL) was added methylmagnesium bromide (in ether, 3 M, 2.7 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours, then quenched with saturated aqueous NH4Cl, and extracted with Et2O. The combined extracts were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated to give the tile compound for the next step.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[NH:6][CH:7]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:17][C:18]1[N:23]=[C:22]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[NH:6][CH:7]=[C:3]([C:2]([F:1])([F:15])[F:16])[N:4]=2)[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccccc1-c1nc(C(F)(F)F)c[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1c[nH]c(-c2ccccc2Nc2nc(Cl)ncc2Cl)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
2-(4-Trifluoromethyl-1H-imidazol-2-yl)-phenylamine (0.200 g, 0.880 mmol) and 2,4,5-Trichloro-pyrimidine (0.161 g, 0.880 mmol) were dissolved in N,N-Dimethylformamide (5.0 mL) and the reaction was heated at 50° C. and was allowed to stir overnight. The reaction mixture was poured over saturated ammonium chloride, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 220 mg (67%) of the desired product.