Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[N:25]=1.[F:48][CH2:49][CH2:50][NH:51][C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH:56]=1)=[O:53]>>[F:36][C:34]1[CH:33]=[CH:32][C:31]([S:37]([CH3:40])(=[O:39])=[O:38])=[C:30]([C:28]2[N:27]=[C:26]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]3[CH3:47])[N:25]=[C:24]([C:58]3[CH:57]=[CH:56][C:55]([NH:54][C:52]([NH:51][CH2:50][CH2:49][F:48])=[O:53])=[CH:60][CH:59]=3)[CH:29]=2)[CH:35]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCF)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Yield: 22 %

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-2-yl)-3-methylmorpholine (intermediate 16) and 1-(2-fluoroethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 19). Material was purified by prep HPLC (low pH) to afford a brown solid. Further purification was achieved using an SCX-2 cartridge to afford a brown solid (50 mg, 22%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[N:10]=[N:11][N:12]([CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:19].[F:20][C:21]1[CH:22]=[CH:23][C:24](B2OC(C)(C)C(C)(C)O2)=[C:25]2[C:29]=1[C@H:28]([O:30][C:31]1[CH:44]=[CH:43][C:34]3[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=3[CH:32]=1)[CH2:27][CH2:26]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([C:9]3[N:10]=[N:11][N:12]([CH2:14][C:15]([OH:17])([CH3:18])[CH3:16])[N:13]=3)=[CH:4][C:3]=2[CH3:19])=[C:25]2[C:29]=1[C@H:28]([O:30][C:31]1[CH:44]=[CH:43][C:34]3[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=3[CH:32]=1)[CH2:27][CH2:26]2
Reactant: Cc1cc(-c2nnn(CC(C)(C)O)n2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nnn(CC(C)(C)O)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 1-(5-(4-bromo-3,5-dimethylphenyl)-2H-tetrazol-2-yl)-2-methylpropan-2-ol and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 15): tR=1.24 min; Mass spectrum (ESI+): m/z=587 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O[CH2:13][C@@H:14]1[CH2:18][N:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=3[CH:29]=2)[C:16](=[O:30])[CH2:15]1.[N-:31]=[N+:32]=[N-:33].[Na+].O>N1C=CC=CC=1.ClCCl>[N:31]([CH2:13][C@@H:14]1[CH2:18][N:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=3[CH:29]=2)[C:16](=[O:30])[CH2:15]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1COc2ccc(N3C[C@@H](CO)CC3=O)cc2N1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reaction time: 24 h
Yield: 65.3 %

Procedure:
p-Toluenesulfonyl chloride (611 mg, 3.20 mmol) was added at room temperature to a solution of 6-[(4S)-4-(hydroxymethyl)-2-oxopyrrolidin-1-yl]-2H-1,4-benzoxazin-3(4H)-one (420 mg, 1.60 mmol) in pyridine (5 ml) and the mixture was stirred for 24 hours. The reaction solution was concentrated under reduced pressure and the obtained resultant was dissolved in dichloromethane and washed with 1N hydrochloric acid. The aqueous layer was extracted with dichloromethane and the organic layer was washed sequentially with water and a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained brown solid was dissolved in N,N-dimethylformamide (5 mL), sodium azide (208 mg, 3.20 mmol) was added thereto and the mixture was stirred at 80° C. for 2 hours. After adding water, the reaction solution was poured into a mixture of dichloromethane and a saturated sodium hydrogen carbonate aqueous solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. Dichloromethane was added to the obtained residue to prepare a slurry and the solid was collected by filtration to yield 300 mg of the title compound in the form of a light yellow solid. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (dichloromethane/methanol) to yield 132 mg of the title compound in the form of a light yellow solid. Total yield 432 mg (94%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.C(OCC)C>C(O)C>[Cl:12][C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[C:3]1[N:30]=[C:28]([NH:27][C:17]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:15]([O:14][CH3:13])[CH:16]=2)[S:29][CH:2]=1
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCOCC
Solvent: CCO
Product: COc1cc(Nc2nc(-c3cc(Cl)ccc3Cl)cs2)ccc1-n1cnc(C)c1
Yield: 100.5 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 89 mg (0.33 mmol) 2-bromo-1-(2,5-dichlorophenyl)ethanone and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was stirred with diethyl ether and little ethanol to yield 130 mg (100%) [4-(2,5-dichloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 431.2/433.0 (100/66) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.80 (s, 1H), 9.29 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.51 (d, 1H), 7.45 (d, 1H), 7.15 (d, 1H), 3.93 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[C@H:3]1[C:12]([OH:14])=[O:13].[O:16]([C:23]1[N:28]=[C:27]([CH2:29]O)[CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCCCCC>[CH3:15][C:2]1([CH3:1])[CH:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]1[C:12]([O:14][CH2:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:28]=1)=[O:13]
Reactant: CC(C)CON=C[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1cccc(Oc2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)CON=CC1C(C(=O)OCc2cccc(Oc3ccccc3)n2)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a stirred solution of 0.75 g of (1R,cis)-2,2-dimethyl-3-((isobutoxyimino)methyl)cyclopropanecarboxylic acid, 0.71 g of 6-phenoxy-2-pyridinemethanol and a catalytic amount of 4-dimethylaminopyridine in 40 ml of methylene chloride under argon was added as one portion 1.19 g of N,N-dicyclohexylcarbodiimide. The reaction mixture was stirred at ambient temperature overnight, then diluted with an equal volume of hexane, filtered and stripped. The resulting oil was dissolved in hexane, filtered, washed with dilute potassium carbonate solution, dried and stripped. The crude product was chromatographed using 20% diethyl ether in hexane as eluent to yield 1.0 g of the desired product.
Reaction SMILES: [CH2:1]([C:5]1([O:12][Si:13]([C:16](C)(C)C)([CH3:15])[CH3:14])[CH2:9][C:8](=[O:10])[C:7]([Cl:11])=[CH:6]1)[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].[O:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:5]1([O:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:9]([CH:29]([OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:8](=[O:10])[C:7]([Cl:11])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)CCCCCC=O
Reactant: CCCCC1(O[Si](C)(C)C(C)(C)C)C=C(Cl)C(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1(O[Si](C)(C)C)C=C(Cl)C(=O)C1C(O)CCCCCC(=O)OC
Temperature: -78 °C
Yield: 33 %

Procedure:
54 mg of 4-butyl-4-t-butyldimethylsilyloxy-2-chloro-2-cyclopentenone was dissolved in 2 ml of dry tetrahydrofuran, and the solution was cooled to -78° C. With stirring, a lithium diisopropyl amide solution was added. At -78° C., the mixture was stirred for 30 minutes. A solution of 50 mg of methyl 7-oxoheptanoate in 1 ml of dry tetrahydrofuran was added, and the mixed solution was stirred at -78° C. to -50° C. for 1 hour. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was chromatographed on a silica gel column (silica gel 30 g; hexane:ethyl acetate=50:1→10:1) to give 29 mg (yield 33%) of a low polarity isomer of 4-butyl-2-chloro-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-trimethylsilyloxy-2-cyclopentenone and 17 mg (yield 20%) of its high polarity isomer.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].O.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>O1CCCC1.O>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1)=[O:5]
Reactant: Nc1nnn[nH]1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cccc([N+](=O)[O-])c1Cl
Reaction time: 1 h

Procedure:
Similarly, a solution of 109 g of 2-chloro-3-nitrobenzoyl chloride in 100 ml of tetrahydrofuran was reacted with a mixture of 103 g of 5-aminotetrazole monohydrate in 1200 ml of hot tetrahydrofuran and 50 ml of water. A voluminous precipitate appeared and, after 1 hour, the mixture was diluted with 2 liters of water and the resulting white solid was collected and oven-dried to give 2-chloro-3-nitro-N-(1H-tetrazol-5-yl)-benzamide melting at about 279° C. with decomposition. In this case, the indicated acid chloride was obtained by the reaction of 2-chloro-3-nitrobenzoic acid with phosphorus pentachloride in cyclohexane. The acid chloride melts at about 57°-59° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1([CH3:40])[CH2:30][CH2:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.[Cl-].C(N)CC1C=CC=CC=1.[Pd+2].[Cl-]>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:28]1[CH2:29][CH2:30][C:25]([CH3:40])([CH3:24])[CH2:26][CH:27]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1Cl
Agent: [Pd+2]
Agent: NCCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1C1=CCC(C)(C)CC1
Temperature: 110 °C
Yield: 40.1 %

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate (74 mg, 0.22 mmol) and 2-(4,4-dimethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (78 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added potassium phosphate (153 mg, 0.66 mmol) and (2-dicyclohexyl-phosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) chloride methyl-t-butyl ether adduct, (SPhos) palladium(II) phenethylamine chloride (15 mg, 0.022 mmol) and the reaction was degassed 10 minutes with argon. The reaction was heated to 110° C. for 1 hour in a microwave reactor. The crude reaction was absorbed onto silica and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a clear white oil (36 mg). 1H-NMR: 400 MHz, (CDCl3) δ: 7.83-7.78 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.53 (s, 1H), 7.43-7.36 (m, 2H), 5.66-5.61 (m, 2H), 4.20-4.03 (m, 2H), 2.66-2.60 (m, 2H), 2.26-2.03 (m, 4H), 1.87-1.59 (m, 5H), 1.24-1.20 (m, 9H), 1.19-1.11 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.C(N(CC)CC)C.[F:35][C:36]([F:42])([F:41])[S:37](Cl)(=[O:39])=[O:38].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][S:37]([C:36]([F:42])([F:41])[F:35])(=[O:39])=[O:38])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of 4-[2-methyl-4-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-sulfonyl]-phenol (122 mg, 0.318 mmol), prepared by the method described in Example 2, and triethylamine (0.053 mL, 0.38 mmol) in CH2Cl2 (3 mL) was added trifluoromethanesulfonyl chloride (0.037 mL, 0.35 mmol) at 0° C. The reaction mixture was stirred under N2 and slowly warmed to room temperature. The mixture was treated with saturated aqueous NaHCO3, and extracted (3×) with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (67:33 hexanes/EtOAc) to provide trifluoromethanesulfonic acid 4-[2-methyl-4-(2,4,6-trimethylphenylamino)-pyrimidine-5-sulfonyl]-phenyl ester (150 mg, 91%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.79 (s, 1H), 8.15 (br s, 1H), 8.08 (d, J=8.9 Hz, 2H), 7.47 (d, J=8.9 Hz, 2H), 6.92 (s, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 1.98 (s, 6H); ESI MS m/z 516 [(M+H)+, calcd for C21H21F3N3O5S2, 516.1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.OS(O)(=O)=O.[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([O:13][CH3:19])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) (1.6 Kg, 6.6 mol) in anhydrous MeOH (32 L) was added H2SO4 (160 mL). The reaction was slowly heated to 70° C. and stirred for 20 hours. The solution was concentrated under vacuum to a volume of 1.6 L. The residue was partitioned between DCM (120 L) and aqueous 10% NaHCO3 (32 L). The organic phase was separated and washed with aqueous 25% NaCl (32 L), dried over Na2SO4 and concentrated to a volume of 4.8 L. The product was crystallized by charging the solution with 3×n-heptane (8 L) while concentrating the volume to 4.8 L after each addition of n-heptane. The solid was filtered and dried under vacuum at 50° C. to produce methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (1.53 Kg, 6.0 mol, 80.6% purity, 90.4% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 3.95 (s, 3H), 8.62 (d, J=2 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H), 14.78 (brs, 1H); ESIMS found C8H6BrN3O2 m/z 256.0 (M+H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:22]([O:21][C:19]([C:15]1([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:18][CH2:17][CH2:16]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(N2CCN(C(=O)OC(C)(C)C)CC2)CCC1
Temperature: 85 °C
Yield: 26.4 %

Procedure:
Tert-Butyl piperazine-1-carboxylate (0.50 g, 2.7 mmol) and ethyl 1-bromocyclobutanecarboxylate (0.52 ml, 3.2 mmol) were dissolved in DMF (5 ml). Potassium carbonate was added, and the mixture was heated to 85° C. for 24 h. The mixture was diluted with brine and then extracted twice with EtOAc. Combined organic layers were washed once with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, gradient, 45-55% EtOAc/hexanes) to give tert-butyl 4-(1-(ethoxycarbonyl)cyclobutyl)piperazine-1-carboxylate as a colorless oil (223 mg, 27%).
Reaction SMILES: Cl.N1C=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC)(OC)(OC)CCC.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][CH2:31][CH2:32][C:33]2[O:37][N:36]=[C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:34]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([CH2:4][CH2:5][CH3:6])[N:30]([CH2:31][CH2:32][C:33]3[O:37][N:36]=[C:35]([C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)[CH:34]=3)[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: c1ccncc1
Reactant: Nc1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Agent: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc2c(Cl)nc3ccccc3c2n1CCc1cc(-c2ccc(F)cc2)no1
Yield: 51.1 %

Procedure:
Under a nitrogen atmosphere, pyridine hydrochloride (1.6 g, 14 mmol), trimethyl orthobutyrate (1.62 g, 11.0 mmol), 2-chloro-N4-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}quinoline-3,4-diamine (2.10 g, 5.49 mmol), and toluene (50 mL) were combined and heated at reflux for four hours under a Dean-Stark trap. The volatiles were removed under reduced pressure. The resulting oil was dissolved in ethyl acetate, and the solution was washed sequentially with aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 4:6 hexane:ethyl acetate) to provide 1.22 g of 4-chloro-1-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-2-propyl-1H-imidazo[4,5-c]quinoline as a pale yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+].O(C1C=C(CC(NCC2C=C(C3C=CC=CC=3C(F)(F)F)C=CC=2)(O)C(F)(F)F)C=CC=1)C1C=CC=CC=1>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([F:42])([F:41])[F:30])[CH:26]=[CH:27][CH:28]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: OC(CN(Cc1cccc(-c2ccccc2C(F)(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F

Procedure:
To a toluene (8 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol (0.51 g, 1.1 mmol) from EX-595B added 2-(tri-fluoromethyl)phenylboronic acid (0.33 g, 1.7 mmol) and DMF 3 mL). To the resulting solution was added K2CO3 (0.31 g, 2.2 mmol) and Pd(PPh3)4 (0.060 g, 0.05 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.32 g (55%) of the desired 3-[(3-phenoxyphenyl)[[(2′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]methyl]amino]-1,1,1-tri-fluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H23NO2F6.0.8 EtOH: C, 64.67; H, 4.93; N, 2.46. Found: C, 64.53; H, 4.69; N, 2.49. HRMS calcd. 532.1711 [M+H]+. found: 532.1708. 1H NMR (C6D6) δ 1.72 (d, 1H), 3.17 (dd, 1H), 3.46 (dd, 1H), 3.72 (m, 1H), 4.23 (s, 2H), 6.33 (dd, 1H), 6.43 (dd, 1H), 6.52 (t, 1H), 6.82 (m, 2H), 6.9-7.1 (m, 11H), 7.43 (d, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:13]=[N:12][C:11]2[N:10]3[CH2:14][CH2:15][CH2:16][CH:9]3[CH2:8][C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[N:18]1([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CS(C)=O>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:21]3[CH2:20][CH2:19][N:18]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[CH2:23][CH2:22]3)[CH:13]=[N:12][C:11]=2[N:10]2[CH2:14][CH2:15][CH2:16][CH:9]2[CH2:8]1
Reactant: O=C1CC2CCCN2c2ncc(CO)cc2N1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)CC3CCCN43)CC2)cc1
Temperature: 90 °C
Yield: 72 %

Procedure:
3-(hydroxymethyl)-7a,8,9,10-tetrahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one (100 mg, 0.429 mmol), 4-(piperazin-1-yl)benzonitrile (96 mg, 0.514 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.685 mmol) and N,N-diisopropylethylamine (0.374 mL, 2.141 mmol) were suspended in propiononitrile (Volume: 2 mL) and heated in a closed vial at 90° C. for 5 h. The reaction mixture was cooled, diluted with DMSO (2 mL) and purified using preparative HPLC (basic phase, 25-95% ACN). The fractions containing product were concentrated in vacuo and crystallized from water (5 mL). The precipitate was filtered and dried in vacuum to afford 4-(4-((6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-3-yl)methyl)piperazin-1-yl)benzonitrile (124.2 mg, 0.309 mmol, 72.1% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.65 (m, 1H) 1.72-1.86 (m, 1H) 1.87-1.97 (m, 1H) 2.14 (qd, J=5.81, 4.04 Hz, 1H) 2.40-2.48 (m, 4H) 2.52-2.59 (m, 1H) 2.66 (dd, 1H) 3.30 (br. s., 4H) 3.33-3.40 (m, 2H) 3.45-3.54 (m, 1H) 3.66 (td, J=10.61, 6.82 Hz, 1H) 3.88 (td, J=9.47, 6.06 Hz, 1H) 7.00 (d, J=9.35 Hz, 2H) 7.14 (d, J=2.02 Hz, 1H) 7.57 (d, J=9.09 Hz, 2H) 7.75 (d, J=2.02 Hz, 1H) 9.56 (d, 1H). [M+H] calc'd for C23H26N6O, 402. found, 402.