Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH:15]=[O:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])([CH3:4])([CH3:3])[CH3:2].P([O-])(O)(O)=[O:27].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:14])([C:15]([OH:27])=[O:16])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:6]=1[O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=P([O-])(O)O
Reactant: CC1(C=O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1(C(=O)O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a solution of 0.5 g of 4,6-di-t-butyl-2-formyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran in 5 ml of t-butyl alcohol were added 5 ml of a saturated aqueous sodium dihydrogenphosphate solution and 0.73 ml of 2-methyl-2-butene, and the mixture was cooled to -5° C. To this solution was added dropwise a solution of 0.14 g of sodium chlorite in 5 ml of distilled water, and the mixture was stirred for 20 minutes, then further stirred at room temperature for 15 minutes. The reaction solution was extracted with diethyl ether, and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was recrystallized from hexane to give 0.38 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid as a colorless powder (yield 73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:21]3)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][C:22]([N:28]2[CH2:29][CH2:30][N:31]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:32][CH2:33]2)=[N:21]3)=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(Nc1cc(-c2ccc3ncc(N4CCNCC4)nc3c2)cnc1Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 6.1 %

Procedure:
To a solution of N-{2-chloro-5-[3-(1-piperazinyl)-6-quinoxalinyl]-3-pyridinyl}benzenesulfonamide (0.23 mmol), triethylamine (0.92 mmol), in dichloromethane (5 ml) was added methanesulfonyl chloride (0.25 mmol), which stirred at 50° C. for 18 hours. The reaction was cooled to ambient temperature, concentrated, redissolved in methanol and purified on reverse phase HPLC (0.1% ammonium hydroxide/water in acetonitrile). The desired fractions were combined and concentrated to give the title compound (7.8 mg, 2%) as a white solid. MS(ES)+ m/e 560.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)=[O:20]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Reactant: Nc1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Nc2ccc(O)cc2)C(C)(C)CCC1
Reaction time: 1 h

Procedure:
A mixture of all-trans retinoic acid (ATRA) (200 mg, 0.66 mmol) in dry DMF (2 mL) and dry CH2Cl2 (2 mL) was stirred under nitrogen atmosphere for 1 h. Oxalyl chloride (2.5 mmol, 215 μL) was added drop by drop at 0° C. The deep red reaction mixture was stirred for another 1.5 h at room temperature under nitrogen atmosphere. Very carefully removed the solvent, then added dry DMF (2 mL) for immediate use. At 0° C. under nitrogen atmosphere, Retinoyl chloride solution was added dropwise to a solution of 4-aminophenol (1.331 mmol, 145.3 mg) and triethylamine (1.997 mmol, 280 μL) in dry DMF (2 mL). The dark-colored reaction mixture was stirred at room temperature until TLC analysis indicated none remaining (about 2˜3 h). The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The extracts were washed with H2O and brine, then dried overage Na2SO4, and evaporated. The residue was purified by flash column chromatography using hexane/ethyl acetate (3/1) as the eluent to give 4-HPR as a yellow solid. 1H-NMR(300 MHz, CDCl3): δ7.42 (d, 2H), 7.11 (s, 1H), 6.99 (dd, 1H), 6.83 (d, 2H), 6.33˜6.18 (m, 4H), 5.80 (s, 1H), 2.44 (s, 3H), 2.04 (br s, 5H), 1.74 (s, 3H), 1.64˜1.62 (m, 2H), 1.33 (m, 2H), 1.05 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17](OC)=[O:18])([C:13](OC)=[O:14])[CH2:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:17][OH:18])([CH2:13][OH:14])[CH2:10][C:9]=2[C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C(=O)OC)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC(CO)(CO)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
Under nitrogen, a solution of 1.01 g (2.34 mmol) of 1-[2-(4-fluorophenyl)-4,4-dicarbomethoxycyclopenten-1-yl]-4-(methylsulfonyl)benzene (prepared in Step 8) in 1.5 mL of THF at -78° C. was treated with 11.6 mL (11.6 mmol) of DIBAL (1.0M in THF). The reaction was stirred at ambient temperature for 1.5 hours, quenched with acetone and aqueous NaOH, extracted with ethyl acetate, dried (MgSO4), and concentrated in vacuo to give 840 mg of crude 1-[2-(4-fluorophenyl)-4,4-di(hydroxymethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene as a colorless oil: NMR (CDCl3) δ 2.82 (d, J=5 Hz, 4H), 3.04 (s, 3H), 3.86 (d, J=5 Hz, 4H), 6.94 (t, J=9 Hz, 2H), 7.11 (dd, J=5 and 9 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.77 (d, J=9 Hz, 2H).
Reaction SMILES: O[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)([Cl:29])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCOCC>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([Cl:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)C(Cl)Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 10 ml of ether, 350 mg of ethyl 2-hydroxy-3-[4-(2-benzoyl-2-propyloxy)phenyl]propionate, 360 mg of thionyl chloride, and catalytic amount of pyridine are added and stirred at room temperature overnight. Then, saturated aqueous sodium bicarbonate solution is added and the ether layer separated is dried, evaporated, and purified with column chromatography. Ethyl-2-chloro-3-[4-(2-benzoyl-2-propyloxy)phenyl]propionate is obtained with the yield of 300 mg. In IR and NMR, this product is in good agreement with the compound No. 1 in Example 7.
Reaction SMILES: [C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([OH:12])[CH:7]=[CH:6][C:4]=1[OH:5])#[N:2].[OH-].[K+].[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CO.CN(C)C=O>[C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6][C:4]=1[OH:5])#[N:2]
Reactant: CCCCCCBr
Reactant: N#Cc1c(O)ccc(O)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(O)c(C#N)c1C#N
Temperature: 50 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
27 g (168.8 mM) of 2,3-dicyanohydroquinone and 22.2 g (337 mM) of 85%-potassium hydroxide were dissolved in a mixture solvent of 65 ml of methanol and 302 ml of dimethylformamide, followed by heating to 50° C. To the solution, 33.4 g (202.4 mM) of hexyl bromide were added dropwise in 25 minutes, followed by heating to 100° C. and stirring for 3 hours. The reaction mixture was poured into cold water and washed with ether. The water layer was acidified with 6N-hydrochloric acid to provide a pH value of 1, followed by precipitation of a crystal. The crystal was extracted with ether, and the ether layer was washed with 5%-sodium hydrogen-carbonate aqueous solution and further washed with water, followed by distilling-off of the solvent to obtain a crude product. The crude product was treated with activated carbon and recrystalized from methanol to obtain 13.1 g of 2,3-dicyano-4-hexyloxyphenol.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:37])[C:8]1=[O:38])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:38])[N:9]([CH3:37])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)=[CH:35][CH:34]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3ccc(C(F)(F)F)nc3)cnc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3ccc(C(F)(F)F)nc3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(6-(trifluoromethyl)pyridin-3-yloxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (20 mg, 0.036 mmol) in THF (2 mL) and water (2 mL) was added LiOH.H2O (4.6 mg, 0.109 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 filtered and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(6-(trifluoromethyl)pyridin-3-yloxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6.5 mg, 34.2% yield) as a white solid. 1H NMR (CDCl3) δ: 8.44 (d, J=3.2 Hz, 1H), 8.21 (s, 1H), 7.84 (d, J=3.2 Hz, 1H), 7.57 (s, 1H), 7.28-7.24 (overlap with CDCl3, 2H), 7.12 (t, J=8.8 Hz, 2H), 4.25 (t, J=6.0 Hz, 2H), 4.08 (s, 2H), 3.74 (s, 3H), 3.61-3.54 (m, 2H), 2.93 (brd s, 1H), 1.97-1.90 (m, 2H). LCMS: MH+ 521 and TR=2.625 min.
Reaction SMILES: C[O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:14](=[O:26])[O:13][N:12]=2)=[N:8][O:9][N:10]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.O>[OH:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[C:14](=[O:26])[O:13][N:12]=2)=[N:8][O:9][N:10]=1
Reactant: COCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1onc(-c2nonc2NCCO)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.8 %

Procedure:
In a round bottom flask under nitrogen atmosphere, 3-{4-[(2-methoxyethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one (1.3 g, 3.6 mmol) was stirred in dichloromethane (11 mL). The temperature was brought to −78° C. and a solution of 1.0 M boron tribromide in dichloromethane (7.9 mL, 7.9 mmol) was added dropwise over 15 minutes. The reaction was warmed to room temperature over 45 minutes and continued to stir at room temperature for an additional 45 minutes. The reaction was cooled to 0° C. and a saturated solution of sodium bicarbonate in water (25 mL) was added dropwise over 15 minutes. After warming to room temperature, ethyl acetate (10 mL) and water (10 mL) were added to the flask. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2×20 mL). After drying the combined organic layers over sodium sulfate, the solvent was removed in vacuo to give the desired product (1.0 g, 81%). LCMS calculated for C13H11F3N5O4 (M+H)+: m/z=358.0. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.93 (t, J=8.2 Hz, 2H), 7.79 (t, J=8.2 Hz, 1H), 6.35 (t, J=5.7 Hz, 1H), 4.86 (br s, 1H), 3.55 (t, J=6.0 Hz, 2H), 3.28 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:13]([CH2:14][CH:15]([CH3:17])[NH2:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30][Cl:31])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:31].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][CH:15]([NH:16][CH2:30][CH2:29][CH2:28][CH:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:17])=[CH:18][CH:19]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: CC(N)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 60 h

Procedure:
The mixture of 11.1 g of dl-p-benzyloxyamphetamine hydrochloride, 11.2 g of 4,4-di-(4-fluorophenyl)-butyl chloride, 10.34 g of diisopropyl-ethylamine and 50 ml of dimethylformamide is stirred at 100° for 60 hours. It is evaporated, the residue taken up in benzene and the solution washed three times with water. The organic layer is dried, evaporated, the residue taken up in diethyl ether and the solution acidified with hydrogen chloride in isopropanol to afford the dl-1-(p-benzyloxyphenyl)-2-[4,4-di-(4-fluorophenyl)-butylamino]-propane hydrochloride, melting at 130°-133°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]([OH:14])=[O:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C>O1CCCC1.CCCCCC>[C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:23])[OH:21])=[CH:3][CH:4]=1)([OH:14])=[O:13]
Reactant: COB(OC)OC
Reactant: CC(C)(Cc1ccc(Br)cc1)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(Cc1ccc(B(O)O)cc1)C(=O)O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1-bromo-4-(2-carboxy-2-methylpropyl)benzene (1.93 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -70° C. A 1.25M solution of n-butyl lithium in hexane (18 ml) was added dropwise with stirring under an argon atmosphere, such that the temperature did not exceed -65° C. After a further 20 minutes, trimethyl borate was slowly added at -65° C. and the reaction mixture was allowed to attain -15° C. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (50 ml) and the mixture acidified by the addition of 2M hydrochloric acid. The organic phase was separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic phase was washed with brine (15 ml) and evaporated and the residue was triturated with hexane to give 4-(2-carboxy-2-methylpropyl)benzeneboronic acid (1.2 g); 1H NMR (DMSO-d6): 1.06 (s, 6H), 2.78 (s, 2H), 7.11 (d, 2H), 7.67 (d, 2H), 7.9 (br s, 2H), 12.2 (br s, 1H); mass spectrum (-ve ESP) 221 (M-H)-.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:25][C:26]1[S:30][C:29]([CH2:31]Cl)=[CH:28][CH:27]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3SC(Cl)=CC=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][C:29]3[S:30][C:26]([Cl:25])=[CH:27][CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccc(Cl)s1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(Cl)s3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc(Cl)s3)c3c2CCNCC3)cc1
Yield: 38.3 %

Procedure:
The title compound (0.029 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 5-chloro-thiophen-2-ylmethyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(5-chloro-thiophen-2-ylmethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C18H17Cl2N3S, 377.05. found, m/z 378.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.49-7.46 (m, 2H), 3.91 (d, J=3.8 Hz, 1H), 6.86 (d, J=3.8 Hz, 1H), 5.51 (s, 2H), 3.45-3.44 (m, 2H), 3.38-3.61 (m, 2H), 3.27-3.25 (m, 2H), 3.07-3.05 (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[C:19](=O)(O)[O-:20].[Na+]>CN(C)C=O>[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([CH:19]=[O:20])=[CH:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(-n2cccc2Cl)cc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-n2c(Cl)ccc2C=O)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Phosphoryl chloride (747 μl) was added dropwise to N,N-dimethylformamide (7 ml) at 5° C. The mixture was stirred at 5° C. for 15 minutes and at ambient temperature for 15 minutes. To the mixture was added a solution of 2-chloro-1-(4-methylphenyl)pyrrole (1.2 g) in N,N-dimethylformamide (7 ml) at ambient temperature. The mixture was stirred at the same temperature for one hour and at 50° C. for 2.5 hours. After cooled to ambient temperature, the mixture was treated with saturated aqueous sodium bicarbonate solution. The separated oil was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated in vacuo. The residue was column chromatographed on silica gel to yield 5-chloro-1-(4-methylphenyl)pyrrole-2-carbaldehyde (377 mg) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:13]([C:14]([N:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)=[O:15])[C:12]([Cl:18])=[CH:11][C:10]=1[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Cl
Reactant: CN1CCNCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)OCc3ccccc3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 5-(benzyloxy)-4-((benzyloxy)carbonyl)-2-chlorobenzoic acid (may be prepared as described in D74) (500 mg, 1.260 mmol) in N,N-Dimethylformamide (DMF) (5 mL) were added DIPEA (0.660 mL, 3.78 mmol), 1-methylpiperazine (0.182 mL, 1.638 mmol), 1-hydroxy-7-azabenzotriazole (206 mg, 1.512 mmol) and EDC (435 mg, 2.268 mmol). The mixture was stirred at room temperature for 8 hrs. The solvent was removed in vacuo. The residue was redissolved in DCM (10 mL) and washed with water (10 mL), dried over MgSO4 and concentrated in vacuo. Purification by column (Si, Isolute, 10% 2M NH3 in MeOH/DCM) gave the title product as a yellow solid (400 mg, 66% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].CCOC(C)=O>C1COCC1.O.[Cl-].[Na+].O>[CH2:16]([O:15][C:13](=[O:14])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Br)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 107.6 %

Procedure:
A solution of 4-bromobenzylamine (5 g, 26.9 mmol) in THF (50 ml) and water (50 ml) was cooled down to 0° C. with sodium hydroxide (1.13 g, 28.2 mmol). Benzyl chloroformate (4.0 ml, 28.2 mmol) was added slowly and the reaction mixture was stirred at 0° C. for 1 h and at r.t. for 18 hours. Brine (50 ml) and EtOAc (50 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (40 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to yield a light pink solid (9.27 g, 100%). 1H NMR (300 MHz, CDCl3), δ: 4.34 (2 H, d, J=6.0 Hz, CH2NH), 5.14 (2 H, s, OCH2), 7.17 (2 H, d, J=8.1 Hz, Ar), 7.33-7.40 (5 H, m, Ar), 7.46 (2 H, d, J=8.3 Hz, Ar)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH:24]=1.C(O)(=O)C>C(O)C>[ClH:1].[C:13]([C@:10]1([CH:15]2[CH2:17][CH2:16]2)[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH:24]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: N#C[C@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CNC(=O)Cn1cc(N)cn1
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(=O)Cn1cc(Nc2nccc(N3CC[C@](C#N)(C4CC4)C3=O)n2)cn1
Product: Cl
Yield: 58.2 %

Procedure:
A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (130 mg) obtained in Step A of Example 105, 2-(4-amino-1H-pyrazol-1-yl)-N-methylacetamide (84 mg) and acetic acid (31 μL) in ethanol (3.0 mL) was stirred in a microwave reactor at 160° C. for 1 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). To a solution of the residue (180 mg) in ethanol (5.0 mL) was added 1 M hydrochloric acid (0.50 mL), and the solvent was evaporated under reduced pressure. The residue was recrystallized (diisopropyl ether/ethanol) to give the title compound (120 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:28]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2([C:26]#[N:27])[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH2:17]2)=[CH:14][CH:15]=1)=[O:8].[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:26]([C:16]1([C:13]2[N:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:28]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)[CH:3]=[N:4][CH:5]=3)=[CH:15][CH:14]=2)[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][CH2:17]1)#[N:27]
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#CC1(c2ccc(NC(=O)c3cncc(Br)c3)cn2)CCC2(CC1)OCCO2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(NC(=O)c3cncc(-c4ccc(F)cc4)c3)cn2)CCC2(CC1)OCCO2
Temperature: 100 °C
Reaction time: 6 h
Yield: 15 %

Procedure:
A solution of 5-bromo-N-[6-(8-cyano-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]nicotinamide (213 mg), 4-fluorophenylboronic acid (63 mg), bis(triphenylphosphine)palladium (II) dichloride (100 mg) and sodium carbonate (636 mg) in a mixture of toluene (5 ml), ethanol (1 ml) and water (1 ml) was stirred at 100° C. for six hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography to give the titled compound (31 mg).