Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:9]([CH3:11])=[CH:10][C:3]=12.C([Li])(CC)C.C1CCCCC1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:33]([O:34][CH2:35][CH3:36])=[O:37])=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])[C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: CCOC(=O)Cl
Reactant: Cc1cc2c(Cl)ccnc2n1[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)c1cnc2c(cc(C)n2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C

Procedure:
A solution of 4-chloro-2-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (525 mg) in tetrahydrofuran (10 ml) was cooled to −78° C. under nitrogen atmosphere, and to the reaction mixture was added 0.99M sec-butyllithium/cyclohexane solution (4.1 ml) dropwise. After the mixture was stirred at −78° C., ethyl chlorocarbonate (389 μl) was added dropwise. The reaction solution was stirred at −78° C. for 30 minutes, saturated aqueous ammonium chloride (20 ml) was added, and the temperature was returned to ambient temperature. The reaction solution was transferred into a separating funnel and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane) to obtain ethyl 4-chloro-2-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (645 mg) as a colorless viscous liquid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C(N(CC)CC)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(I)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
4-Iodobenzoyl chloride (10.0 g) was added portionwise to piperidine (3.53 g) in triethylamine (40 ml) at 0° and the suspension was stirred at room temperature under nitrogen for 1 h. The reaciton mixture was poured into 2N aqueous hydrochloric acid (200 ml) and extracted with EA (3×100 ml). The combined extracts were washed with water (100 ml), 8% aqueous sodium bicarbonate (100 ml) and water (10 ml), dried and concentrated. The resultant solid (10.25 g) was purified by FCC eluting with ER-H (1:2→1:1) to give the title compound as a white solid (9.33 g) m.p. 126°-127°.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)CCCSCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCSCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
Sodium borohydride (1.0 mg, 0.026 mmol), followed by MeOH (0.1 mL), was added to a solution of 4-{2-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-ethylsulfanyl}-butyric acid methyl ester (6.8 mg, 0.017 mmol) in CH2Cl2 (0.3 mL) at 0 ° C. After 15 min at 0° C., the reaction was quenched with aqueous HCl (0.1 M, 4 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 6.8 mg (99%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:8]2[C:9](=[S:45])[NH:10][C:11](=[O:44])[N:12]([CH:43]=2)[C@@H:13]2[O:42][C@H:32]([CH2:33][O:34][Si](C(C)(C)C)(C)C)[C@@H:23]([O:24][Si](C(C)(C)C)(C)C)[C@H:14]2[O:15][Si](C(C)(C)C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:46]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[C:9](=[S:45])[NH:10][C:11](=[O:44])[N:12]([CH:43]=2)[C@@H:13]2[O:42][C@H:32]([CH2:33][OH:34])[C@@H:23]([OH:24])[C@H:14]2[OH:15])[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(c3ccccc3)c3ccccc3)c(=S)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)c(C(c2ccccc2)c2ccccc2)cn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h
Yield: 42.6 %

Procedure:
The product of step (ii) (5.5 g) was treated with 1M tetra-n-butylammonium fluoride in tetrahydrofuran (21.5 ml) at room temperature. After stirring for 2 hours the solvent was removed under reduced pressure and the residue was purified by flash silica-gel chromatography eluting with ethyl acetate/iso-hexane mixtures to afford 5-diphenylmethyl-4-thiouridine as a yellow solid (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[CH:5]=[C:4]([Cl:13])[C:3]=1[NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:17]=1.[BH4-].[Li+]>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:13])[C:3]=1[NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH:17]=1
Reactant: CCOC(=O)c1cc(Cl)c(NC(=O)c2ccc(OC)c(OC3CCCC3)c2)c(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cc(CO)cc2Cl)cc1OC1CCCC1
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A stirred solution of N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide (6.1 g) in dry tetrahydrofuran (80 mL) at room temperature under argon is treated dropwise with a solution of lithium borohydride in tetrahydrofuran (115 mL; 2 M). The mixture is stirred overnight and then it is treated portionwise with saturated brine (200 mL) and stirred for 30 minutes. The organic layer is then washed with water, dried over magnesium sulfate and evaporated. The resulting residue is subjected to flash chromatography on silica gel, to give N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide (4.4 g), m.p. 174–176° C. [Elemental analysis: C, 57.1; H, 5.4; N, 2.9%; calculated C20H21O4NCl2:0.5H2O: C, 57.3; H, 5.3; N, 3.3%]
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH:8]([CH3:10])[CH3:9])[CH:7]=1.[CH:12]([C:14]1[S:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH:8]([N:6]1[C:5](=[O:11])[CH:4]=[CH:3][C:2]([C:17]2[S:18][C:14]([CH:12]=[O:13])=[CH:15][CH:16]=2)=[CH:7]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1cc(I)ccc1=O
Reactant: O=Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)n1cc(-c2ccc(C=O)s2)ccc1=O
Temperature: 100 °C
Yield: 53.5 %

Procedure:
To a stirred solution of 5-iodo-1-isopropylpyridin-2(1H)-one (0.41 g, 1.55 mmol) in toluene (5 mL) and ethanol (2 mL) was added 5-formylthiophen-2-yl boronic acid (0.289 g, 1.87 mmol), 2M Na2CO3 (0.495 g, 4.67 mmol), and Pd(PPh3)4 (0.09 g, 0.07 mmol). The mixture was purged with argon and heated at 100° C. for about 2 h. The mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine solution (20 mL), dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 20% ethyl acetate in hexane as eluent to afford 5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-carbaldehyde as an off-white solid (0.205 g, 53.3% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.99 (d, 1H), 7.78 (d, 1H), 7.62 (d, 1H), 7.58 (d, 1H), 7.53 (d, 1H), 5.08-5.01 (m, 1H), 1.21 (t, 6H), LC-MS m/z calcd for [M+H]+ 248.07. found 248.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([CH3:15])=[O:14])=[C:9]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:21]1(=O)[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1.Cl.CN(C)CCCN=C=NCC.CC1C=CN=C(N)C=1C>C(Cl)Cl>[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([CH3:15])=[O:14])=[C:9]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]=1)=[O:5]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCC(C)=O
Reactant: O=C1CCCC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1OCC(C)=O

Procedure:
0.295 g (0.9 mmol) of 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonylbenzoic acid, 0.113 g (1.0 mmol) of cyclohexane-1,3-dione, 0.180 g (0.9 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.001 g of dimethyl-aminopyridine were stirred in 25 ml of CH2Cl2 at RT for 2 h. The mixture was then diluted with CH2Cl2 and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. The combined organic phases were dried over Na2SO4 and then evaporated to dryness, giving 3-oxo-1-cyclohexenyl 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonylbenzoate in the form of a brown resin which was sufficiently pure for the subsequent reaction.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=O)[NH:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36]>N1C=CC=CC=1>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[S:36])[NH:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
To a mixture of 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4-(1H,3H)-quinazolinedione (3.1 g) and phosphorus pentasulfide (6.1 g) was added pyridine (70 ml) and the mixture was stirred for 18 hours at 100° C. The reaction mixture was cooled and then concentrated in vacuo. To the residue was added water and the mixture was stirred and then resultant precipitates were collected by filtration and washed with water. To the precipitates was added chloroform and the mixture was stirred enough and then insoluble materials were filtered off. These insoluble materials were washed twice with chloroform and then whole chloroform layers were combined, washed with water and with saturated sodium chloride aqueous solution respectively, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by a column chromatography on silica gel (90 g) using 2% methanol in chloroform for elution to give 1-[3-{4-(diphenylmethyl)piperazin1-yl}propyl]-4-thioxo-3,4-dihydro-2(1H)-quinazolinone (1.2 g) as an amorphous material.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][C:15]([CH3:17])=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:32]=[CH:31][C:21]([CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:20][CH:19]=1.BrB(Br)Br>>[NH2:23][CH2:22][C:21]1[CH:31]=[CH:32][C:18]([C:4]2[C:5]3[C:6]4[CH:16]=[C:15]([CH3:17])[S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[OH:2])=[CH:19][CH:20]=1
Reactant: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: Cc1cc2c(s1)c(=O)[nH]c1ccc(O)c(-c3ccc(CN)cc3)c12
Yield: 35 %

Procedure:
Following General Procedure F, tert-butyl 4-(8-methoxy-2-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (80 mg, 0.17 mmol) was reacted with tribromoborane (2.0 mL) to afford the desired product (20 mg, 37%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.63 (d, J=8.9 Hz, 2H), 7.40-7.37 (m, 3H), 7.15 (d, J=8.1 Hz, 1H), 5.76 (s, 1H), 4.28 (s, 2H), 2.33 (s, 3H); ESI MS m/z 337 [C19H16N2O2S+H]+; HPLC >99%, tR=5.91 min.
Reaction SMILES: CN(C)[CH:3]=[O:4].[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[C:27]([OH:28])=[C:26]([O:29][CH3:30])[C:25]([O:31][CH3:32])=[CH:24][C:23]=1C)(=[O:8])[CH3:7]>O=O.C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[C:27](=[O:28])[C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:3](=[O:4])[C:23]=1[CH3:24])(=[O:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(CCCCCCCCCCCCOC(C)=O)c(O)c1OC
Agent: [Co+2]
Agent: O=O
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCOC(C)=O)=C(C)C1=O

Procedure:
To a dimethylformamide solution (20 ml) of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylphenol (1.1 g) is added bis(salicylidene)ethylenediiminocobalt(II) (40 mg) and the mixture is stirred in oxygen streams at atmospheric pressure and temperature for 72 hours. The product is isolated as in Example 7 and recrystallized from etherhexane (1:1). The above procedure yields 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (0.84 g) as orange-yellow needles melting at 47° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:15]=[CH:16][C:17]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.I[CH2:33][CH3:34].[Cl-].[NH4+]>C1COCC1.[Ag].C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:27]([CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH:15]=[CH:16][C:17]=1[B:18]1[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19]1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Reactant: CCI
Agent: [Ag]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(C(=O)OC)c1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (3.86 mL, 3.86 mmol) was added to methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (Intermediate 2-7; 1 g, 3.22 mmol) in THF (10 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 30 minutes. Iodoethane, stabilized with silver (0.258 mL, 3.22 mmol), was added and the reaction stirred for 30 minutes. Ammonium chloride (satd) (25 mL) added with vigorous stirring, ethyl acetate (50 mL) added and the organic phase separated, washed with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoate (0.686 g, 62.9%) as a colourless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C:32]([OH:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C:32]([OH:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C(C)(O)C(=O)O
Product: CCOC(=O)C(C)(O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-hydroxy-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. White solid (>98%). MS: m/e=503(M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:18][Si](C)(C)C.O.[OH-].[Na+]>C(#N)CCC>[Br:18][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Cl)nc2)CCC(F)(F)CC1
Reactant: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCC#N
Product: N#CC1(c2ccc(Br)nc2)CCC(F)(F)CC1
Temperature: 120 °C
Yield: 65.1 %

Procedure:
To a stirred solution of 1-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (1.3 g, 5.1 mmol) in butyronitrile (100 mL) at room temperature under nitrogen atmosphere was added bromotrimethylsilane (1.55 g, 10.2 mmol). The reaction mixture was heated at 120° C. for 24 hours. The reaction mixture was then cooled to room temperature and poured into water (25 mL) and 10% aqueous NaOH solution (25 mL). The aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel to afford 1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile as a white solid (1.0 g, 65%). LC-MS (m/z) 301.0 (MH+). 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (d, J=2.7 Hz, 1 H), 7.69 (dd, J=8.4, 2.8 Hz, 1 H), 7.57 (d, J=8.4 Hz, 1 H), 2.09-2.41 (m, 8 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32](=[O:35])[NH:33]C)[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:32]([CH2:31][N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:35])[NH2:33]
Reactant: CNC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of {(3,5-bis-trifluoromethyl-benzoyl)-[4-(2-chloro-phenyl)-pyridin-3-yl]-amino}-acetic acid (0.15 g, 298 μmol, example 102, intermediate) and EDC (172 mg, 895 μmol) in DMF (2 mL) was treated with 1-hydroxy-7-azabenzotriazole (122 mg, 895 μmol, CAS RN 39968-33-7) and stirred at room temperature for 20 min. to give a yellow solution. Ammonium chloride (160 mg, 2.98 mmol) and DIPEA (386 mg, 521 μL, 2.98 mmol) were added and the reaction was stirred for another 3.75 h. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed twice with water and once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (0.099 g; 66%). MS (ESI): m/z=502.07 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:30]([CH2:38][CH:39]=[CH:40][Cl:41])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Cl:41][CH2:40][CH:39]1[C:2]2[C:11]3[CH:10]=[C:9]([S:12]([N:15]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)(=[O:13])=[O:14])[CH:8]=[CH:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:30]([C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH2:38]1
Reactant: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc21
Yield: 96.3 %

Procedure:
A mixture of 213 (1.00 g, 1.53 mmol), Bu3SnH (550 mg, 1.83 mmol), and AIBN (50 mg, 0.31 mmol) in benzene (25 mL) was heated at reflux for 15 min, then concentrated under reduced pressure. The residue was partitioned between EtOAc and H2O and the EtOAc layer was washed with H2O, brine and dried and evaporated. The residue was purified by chromatography on silica gel, eluting with petroleum ether/EtOAc (9:1) to give tert-butyl 1-(chloromethyl)-8-[(dibenzylamino)sulfonyl]-1,2-dihydro-3H-benzo[e]indole-3-carboxylate (214) (850 mg, 97%). A sample was recrystallised from Et2O/petroleum ether as colorless needles: mp 131-133° C.; 1H NMR (CDCl3) δ 8.30 (br s, 1H), 8.29 (d, J=1.5 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.66 (dd, J=8.6, 1.8 Hz, 1H), 7.23-7.15 (m, 6H), 7.09-7.03 (m, 4H), 4.41 (s, 4H), 4.28 (d, J=11.5 Hz, 1H), 4.15 (dd, J=11.6, 9.0 Hz, 1H), 4.02 (tt, J=9.0, 2.9 Hz, 1 H), 3.75 (dd, J=11.3, 3.5 Hz, 1H), 3.48 (dd, J=11.2, 9.3 Hz, 1H), 1.61 (s, 9H); 13C NMR δ 152.4, 142.7, 138.9, 135.5, 131.3, 130.5, 129.8, 128.9, 128.50, 128.46, 127.7, 124.3, 122.4, 120.3, 118.4, 81.8, 52.7, 50.5, 46.4, 41.4, 28.4. Anal. (C32H33ClN2O4S) C, H, N.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]4)[CH:14]=[N:13][CH:12]=3)[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:41]1[CH:40]=[C:39]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:19][CH2:18]5)[CH:14]=[N:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:43]=[N:42]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(-n3ncc4cnc(Cl)cc43)n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Yield: 41.9 %

Procedure:
A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate (400 mg, 0.93 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (271 mg, 1.4 mmol), Pd(dppf)Cl2 (81 mg, 0.093 mmol) and a solution of Na2CO3 (2.0 M, 1.5 mL) in 1,4-dioxane (6 mL) under argon in a sealed vial was heated at 120° C. for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (10% to 60%) as eluting solvents to afford tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate as yellow solid (180 mg, 42%). MS (ESI) m/z: 462 [M+H]+.