Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:23](OC(=O)C)(=[O:25])[CH3:24].CCOC(C)=O>N1C=CC=CC=1.O>[C:23]([O:1][C@:2]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C[C@](O)(CC=C(C)C)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@](CC=C(C)C)(OC(C)=O)C(=O)OCc1ccccc1

Procedure:
To a solution of tertiary alcohol 77 (33.0 mg, 0.109 mmol, 1.00 equiv) in dry pyridine (500 μL) at 0° C. was added acetic anhydride (114 μL, 1.09 mmol, 10.0 equiv) and N,N-dimethylaminopyridine (DMAP) (3.0 mg, 0.0246 mmol, 0.23 equiv). The solution was then stirred at 23° C. for 17 h at which time further DMAP (13.0 mg, 1.09 mmol, 1.00 equiv) and acetic anhydride (22 μL, 0.21 mmol, 1.9 equiv) were added. After 1 h the solution was diluted with H2O (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with 0.1M aqueous CuSO4 soln, dried over MgSO4, and concentrated by rotary evaporation to yield a dark red oil. Purification by silica gel column chromatography (5:1 hexanes:EtOAc) provided S11 (28.1 mg, 74%) as a colorless oil. Rf=0.32 (5:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.35 (m, 5H, ArH), 5.14 (m, 2H, ArCH2), 5.00 (tt, 1H, J=7.5, 1.3 Hz, vinyl H), 3.64 (s, 3H, CO2CH3), 3.27 (d, 1H, J=14.7 Hz, C(O)CH2), 2.96 (d, 1H, J=14.7 Hz, C(O)CH2), 2.80 (dd, 1H, J=14.6, 7.6 Hz, CHCH2), 2.69 (dd, 1H, J=14.6, 7.6 Hz, CHCH2), 2.06 (s, 3H, C(O)CH3), 1.67 (s, 3H, CCH3), 1.56 (s, 3H, CCH3); 13C NMR (125 MHz, CDCl3) δ 170.34, 170.10, 169.79, 137.21, 135.45, 128.64, 128.50, 128.46, 115.89, 80.51, 67.48, 51.85, 37.41, 34.35, 26.11, 21.09, 18.00; IR (neat film) 3067 (w), 2955 (w), 1746 (s), 1441 (m), 1371 (m), 1227 (m); LRMS (ESI) calcd for C19H24O6Na (M++Na) 371.16; observed 371.00.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27].C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([NH:20][C:26]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: O=C(O)c1ccco1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)c3ccco3)nc2n1
Temperature: 40 °C

Procedure:
A suspension of 3.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine and 1.8 g of 2-furoic acid in 50 ml of chloroform is boiled on a steam bath until the distilling vapors reach a temperature of 61° C. The mixture is cooled to about 40° C. and 2.6 g of carbonyldiimidazole is added cautiously. Gas is evolved. When gas evolution has ceased, the resulting solution is heated at reflux for 30 hours. The cooled reaction mixture is chromatographed directly on a column of 150 g of silica gel. The crude product is eluted with a 99/1 chloroform/methanol mixture. This is purified by trituration with ether and recrystallization of the resulting solid from a chloroform/ether mixture. N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-yl]-2-furancarboxamide is obtained as yellow crystals, mp 228°-230.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[CH2:16][CH2:17][C:18]2[CH2:22][CH:21]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[O:20]N=2)=[CH:4][C:3]=1[CH3:28].B(O)(O)[OH:30]>[Pd].CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[CH2:16][CH2:17][C:18](=[O:30])[CH2:22][CH:21]([OH:20])[CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:4][C:3]=1[CH3:28]
Reactant: COC(=O)CC1CC(CCc2c(C)cc(C)cc2-c2ccc(F)c(C)c2)=NO1
Reactant: OB(O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)CC(O)CC(=O)CCc1c(C)cc(C)cc1-c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.1 g (0.26 mmol) of the isoxazoline from Step E, 50 mg of 10% palladium on carbon catalyst and 48 mg (0.78 mmol) of boric acid in 3 ml of methanol and 0.3 ml of water was stirred under hydrogen (1 atmosphere) at room temperature for 2.5 hours. The mixture was filtered and the filtrate was poured into brine and extracted with ether. The ethereal extract was washed with 5% (w/v) aqueous sodium bicarbonate solution, dried (MgS04), filtered and evaporated to dryness to give 92 mg (0.23 mmol, 89%) as a pale yellow oil. nmr (CDCl3) δ: 2.30 (6H, a methyl singlet and a methyl doublet), 2.33 (3H, s), 2.35-2.5 (6H, m), 2.75-2.85 (2H, m), 3.30 (H, d), 3.70 (3H, s), 4.37 (H, m), 6.83 (H, bs), 6.95-7.1 (4H, m). IR (neat) 3450, 1710 cm-1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:23].Br[CH2:25][C:26]#[N:27].C(N(CC)CC)C>CN(C)C=O.O>[C:26]([CH2:25][N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:23])#[N:27]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1CC1CCCN1
Reactant: N#CCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N#CCN1CCCC1CN1C(=O)Nc2ccccc2C1c1ccccc1
Yield: 98.5 %

Procedure:
A solution of 203 mg (0.66 mmol) of 3-(pyrrolidin-2-yl)methyl-4-phenyl-3,4-dihydro-2(1H)-quinazolinone, 95 mg (0.79 mmol) of bromoacetonitrile and 283 mg (2.8 mmol) of triethylamine in 5 mL of dimethyl-formamide was stirred for 6 hours at 70° C. After being cooled, the reaction mixture was diluted with water, and the mixture was extracted with chloroform. The organic layer separated was washed with water, dried on potassium carbonate and concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 226 mg (0.65 mmol) of the title compound as an about 1:2 mixture of the diastereomers.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:18]O>>[Br:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: O=C(O)C(CCBr)c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(CCBr)c1ccccc1
Temperature: 25 °C

Procedure:
The product of Example 4 (22 g) in methanol (100 ml) was treated dropwise with SOCl2 (7.3 ml, 0.1M) at about 5° C. The reaction mixture was allowed to warm to room temperature. The solvent was evaporated off and the residue partitioned between water and IPE. The organic phase was dried and evaporated to give the title compound as an oil (23 g). Bp. 85°/0.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:9]([NH:11]C(=O)OC(C)(C)C)[CH3:10])=[N+:6]([O-:8])[CH:7]=1.Cl.O1CCOCC1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:9]([NH2:11])[CH3:10])=[N+:6]([O-:8])[CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)c[n+]1[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(F)c[n+]1[O-]
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [(1R)-1-(5-fluoro-1-oxidopyridin-2-yl)ethyl]carbamate (1.47 g, 5.74 mmol) in dichloromethane (28.7 mL) was added 4 M hydrochloric acid in 1,4-dioxane (43.0 mL, 172 mmol). After 2 h, concentration gave the title compound as a hydrochloride salt (1.396 g). MS 157.1 (M+1). 1H NMR (500 MHz, CD3OD): δ 8.55 (dd, J=4.3, 2.4 Hz, 1 H); 7.70 (dd, J=9.0, 6.7 Hz, 1 H); 7.52 (ddd, J=9.1, 7.1, 2.4 Hz, 1 H); 4.80 (q, J=7.0 Hz, 1 H); 1.74 (d, J=7.0 Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C([Li])CCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].O>C1COCC1>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]([Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:7][C:6]=1[O:8][Si:16]([CH3:18])([CH3:17])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc(Br)cc1O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc([Si](C)(C)C)cc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
To a solution of 5-bromo-2-methylphenol (Intermediate 1, 3.6 g, 19.3 mmol) in THF (150 mL) at −78° C. was added n-butyl lithium (30 mL, 1.6 M solution in hexanes, 48.1 mmol) and the reaction stirred at this temperature for 30 minutes. Trimethylsilyl chloride (6.1 mL, 48.1 mmol) was then added and the solution stirred at −78° C. for 1.5 hours. The reaction was allowed to warm to room temperature and water (75 mL) was added. The mixture was extracted with diethyl ether (2×75 mL) and the combined organic extracts were dried (magnesium sulphate) and concentrated under reduced pressure to afford 2-methyl-5-(trimethylsilyl)phenoxytrimethylsilane (5 g) as a yellow oil. 1H NMR δH 0.26 (9 H, s), 0.29 (9 H, s), 2.20 (3 H, s), 6.93 (1 H, d, J=1.1 Hz), 7.04 (1 H, dd, J=7.3, 1.1 Hz), 7.16 (1 H, d, J=7.4 Hz).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)#[N:2].C(=O)([O-])O.[Na+].Cl.[NH2:20][OH:21]>CO>[NH2:2][C:1](=[N:20][OH:21])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: NO
Reactant: COC(=O)c1ccc(CC#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CC(N)=NO)cc1

Procedure:
Methyl 4-(cyanomethyl)benzoate (2.0 g) was suspended in methanol (30 mL), and sodium hydrogen carbonate (0.96 g) and hydroxylamine hydrochloride (0.80 g) were added. The reaction mixture was heated under reflux for 12 hr, and the insoluble material was removed by filtration. The solvent was evaporated under reduced pressure from the obtained filtrate to give the title compound as a bister solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:17]>CCOCC.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(-c2ccc(F)cc2)cc1
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(-c2ccc(CBr)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4'-fluoro-4-biphenylylmethanol (7.38 g, 36.93 mmol) in Et2O (250 ml) is added phosphorous tribromide (7 ml, 73.06 mmol). The reaction is allowed to warm slowly to room temperature and is then refluxed for 12 hours. After the reaction is cooled to room temperature ice chips are added until gas no longer evolves. The reaction mixture is then diluted with H2O (200 ml) and extracted with 1N NaOH (300 ml) and saturated NaCl solution (300 ml), dried over MgSO4, and concentrated in vacuo to give 4'-fluoro-4-biphenylylmethyl bromide as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:28])[C:13]([C:25]([OH:27])=[O:26])=[CH:14][N:15]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[F:29].C[C:31](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:32]>C(O)=O>[CH:31]([N:5]1[CH2:6][CH:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:28])[C:13]([C:25]([OH:27])=[O:26])=[CH:14][N:15]2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[F:29])=[O:32]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(N3CC4CC3CN4)c(F)cc2c1=O
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O=CO
Product: O=CN1CC2CC1CN2c1cc2c(cc1F)c(=O)c(C(=O)O)cn2-c1ccc(F)cc1
Reaction time: 6 h
Yield: 31 %

Procedure:
To 1.2 g (3 m Mol) 7-(2,5-diazabicyclo(2.2.1)hept-2-yl)-6-fluoro-1-(4-fluorophenyl)1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 10 ml of formic acid was added 2.64 g (30 m Mol) of the mixed anhydride of acetic and formic acids and the mixture was stirred for 6 hrs. The volatiles were removed in vacuo and the residue recrystallized to give 0.4 g (31%) of the product, mp 274° C.-276° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]#[C:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([CH2:18][CH2:19][C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:24][CH:25]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 72 h

Procedure:
To a solution of tert-butyl [3-({2-[(tert-butoxycarbonyl)amino]-5-nitrophenyl}ethynyl)phenyl]carbamate (15.0 g, 33.1 mmol) in DMF (234 mL) was added 10% Palladium on carbon (13.1 g, 11.2 mmol). The solution was shaked under 55 psi H2 atmosphere for 72 h. The solution was filtered through a pad of celite. The filtrate was concentrated and purified with silica gel chromatography (45% ethyl acetate/hexanes) to give an intermediate as yellow oil. To a solution of the intermediate in methanol (200 mL) was added 10% Palladium on carbon (12 g). The resulting solution was shaked under 55 psi H2 atmosphere overnight. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The crude product was purified with a short pad of silica gel to give the desire product (11.5 g, 81%). LCMS calculated for C24H33N3O4Na (M+Na)+: m/z=450.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=4)[CH:21]=3)[CH2:16][CH:15]2[C:40](=[O:49])[N:41]([CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=C)[CH3:42])=[O:13])[CH2:8][CH:7]1[CH:9]=C)=[O:5])[CH3:2]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:47][CH2:46][CH2:45][CH2:44][CH2:43][N:41]([CH3:42])[C:40](=[O:49])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=4)[CH:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3cc(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4nc(C(C)C)cs4)nc4cc(OC)ccc34)CC1C(=O)N2
Yield: 73.3 %

Procedure:
1-({2-(Hex-5-enyl-methyl-carbamoyl)-4-[2-(4-isopropyl-thiazol-2-yl)-7-methoxy-quinolin-4-yloxy]-cyclopentanecarbonyl}-amino)-2-vinyl-cyclopropanecarboxylic acid ethyl ester (33, 280 mg) was dissolved in DCE (280 mL) in a reflux setup. The system was successively evacuated and filled with argon (repeated 3 times). Then, Hoveyda-Grubbs 2nd generation catalyst (28 mg) was added and the system was evacuated and filled with argon twice. The resulting mixture was successively heated to refluxed overnight, concentrated, and subjected to flash column chromatography (silica, AcOEt/hexane) to give 197 mg (73%) of the title product 34 as grey-brown solid: m/z=661 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:14])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:15]([O:17][C:18](Cl)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:19])[NH:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[C:4](=[O:14])[CH2:3][C:2]([CH3:1])=[N:6]2)=[CH:8][CH:9]=1)[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: CC1=NN(c2ccc(N)cc2)C(=O)C1
Product: CCOC(=O)Nc1ccc(N2N=C(C)CC2=O)cc1

Procedure:
From the reaction of 5-methyl-2-(4-aminophenyl)-2,4-dihydro-pyrazol-3-one and ethylchloroformate (per the reaction in Example 11) yields N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl-carbamic acid ethyl ester. Subsequent reaction with 2-methoxyaniline yields N-(4-(4,5-dihydro-4-(2-methoxyanilinomethylene)-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)-carbamic acid ethyl ester, Mp: 212° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2=[O:15].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:23][CH3:24])[O:8][C:7]([CH3:13])([CH3:14])[CH2:6][C:5]2=[O:15]
Reactant: CCI
Reactant: CC1(C)CC(=O)c2cc(Br)c(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2

Procedure:
As described in General Procedure A, 6-bromo-7-hydroxy-2,2-dimethyl-chroman-4-one (Compound 3, 2.0 g, 7.35 mmol) was treated with potassium carbonate (500 mg) and iodoethane (1.5 mL, 18.75 mmol) to give rise to the title compound as a white solid after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][NH:8][C:7](=O)[C:6]=2[CH:15]=1.CCN(CC)CC.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:7]1[C:6]2[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Solvent: CCN(CC)CC
Product: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
As illustrated in the scheme above, 7-chloro-3,4-dihydro-1-methyl-1H-1,4-benzodiazepine-2,5-dione (5.00 g, 22.3 mmol) was suspended in POCl3 (100 mL) and heated at 100° C. for 30 min. The reaction was cooled and concentrated in vacuo. Traces of POCl3 were removed by adding toluene and concentrating the mixture in vacuo (2×). The residue was dissolved in CH2Cl2, the solution was cooled to 0° C., and Et3N (6.8 mL, 48.8 mmol) was added dropwise. The mixture was stirred for 1 h and allowed to slowly warm to room temperature, and was then concentrated in vacuo once again. The residue was purified by silica gel column chromatography (5:1 CH2Cl2:EtOAc+0.5% Et3N) to provide the title compound as an orange solid (4.68 g, 86%). 1H-NMR (CDCl3): δ 7.79 (d, J=2.5 Hz, 1H), 7.55 (dd, J=2.4 Hz, J=8.9 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.67 (br s, 1H), 3.72 (br s, 1H), 3.39 (s, 3H). MS (ESI) (M+H)+=243.
Reaction SMILES: [CH:1]1([CH2:5][NH2:6])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:40]([C:44]1[N:48]([CH2:49][CH:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[C:47]2[CH:56]=[CH:57][C:58]([S:60]([N:63]3[CH:67]=[C:66]([C:68](O)=[O:69])[CH:65]=[N:64]3)(=[O:62])=[O:61])=[CH:59][C:46]=2[N:45]=1)([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[C:40]([C:44]1[N:48]([CH2:49][CH:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[C:47]2[CH:56]=[CH:57][C:58]([S:60]([N:63]3[CH:67]=[C:66]([C:68]([NH:6][CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:69])[CH:65]=[N:64]3)(=[O:62])=[O:61])=[CH:59][C:46]=2[N:45]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: NCC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NCC4CCC4)cn3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in example 53, step A, using (cyclobutylmethyl)amine (12 mg, 0.13 mmol), HATU (37 mg, 0.09 mmol), DIPEA (0.02 mL, 0.10 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (40 mg, 0.09 mmol) in DMF (5 mL). The crude product was purified by MPLC on silica gel using EtOAc/DCM (1:1) to provide the title compound as a white solid. The product was converted to its TFA salt. Yield: 27 mg (48%); 1H NMR (400 MHz, CD3OD) δ 1.43-1.51 (m, 3 H), 1.55 (dd, J=12.30, 3.91 Hz, 1 H), 1.61 (s, 9 H), 1.66-1.78 (m, 2 H), 1.81-1.93 (m, 2 H), 1.99-2.10 (m, 2 H), 2.26-2.37 (m, 1 H), 2.48-2.59 (m, 1 H), 3.26-3.36 (m, 4 H), 3.90 (dd, J=11.13, 3.71 Hz, 2 H), 4.45 (d, J=7.42 Hz, 2 H), 7.94-8.04 (m, 2 H), 8.05 (d, J=0.78 Hz, 1 H), 8.36 (d, J=1.37 Hz, 1 H), 8.76 (s, 1 H); MS (ESI) (M+H)+=513.7; Anal. Calcd for C26H35N5O4S+1.8 TFA+2.4H2O: C, 46.65; H, 5.50; N, 9.19. Found: C, 46.74; H, 5.61; N, 8.97.
Reaction SMILES: [Br:1]Br.[C:3]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[C:3]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[CH:18]([Br:1])[CH2:17]2)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: O=C(Oc1cccc2c1C(=O)CC2)c1ccccc1
Solvent: C1CCOC1
Product: O=C(Oc1cccc2c1C(=O)C(Br)C2)c1ccccc1
Reaction time: 0.5 h

Procedure:
0.1 ml of bromine was added dropwise to a solution of 0.47 g of 7-benzoyloxy-1-indanone in tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred for 30 minutes. To 7-benzoyloxy-2-bromo-1-indanone obtained by evaporation of the solvent was added 15 ml of 2-propanol and 0.33 g of 4-imidazolylthioacetamide hydrochloride, followed by 2.5 hours of heating under reflux. After cooling and evaporation of the solvent, the residue was mixed with ethyl acetate, and extracted with 1N hydrochloric acid. The aqueous layer was neutralized with sodium bicarbonate and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residual 4-benzoyloxy-2-(4-imidazolylmethyl)-8H-indeno[1,2-d]thiazole was dissolved in 10 ml of methanol, to the solution was added 1 ml of 5N aqueous sodium hydroxide solution and then stirred at room temperature for 15 minutes. After acidifying with 1N hydrochloric acid, the reaction solution was neutralized with sodium bicarbonate, and extracted with chloroform-methanol, and then the extract was dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resultant crude crystals were recrystallized from ethanol to obtain 55 mg of 4-hydroxy-2-(4-imidazolylmethyl)-8H-indeno[1,2-d]thiazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:36])(=[O:35])[NH:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:44][CH3:45].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:35])(=[O:36])[N:26]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:2][CH2:1][CH2:3][C:45]4[CH:44]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NCCc4ccccc4)C4(CC4)C3)ncnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)N(CCCc4ccccc4)CCc4ccccc4)C4(CC4)C3)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(4-Phenethylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 6) (0.1 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (0.12 mmol) and bromo-ethane (0.12 mmol). Stirred at rt for 16 h and then added H2O (2 mL). Extracted with EtOAc (3×2 mL) and the combined organic phases were concentrated in vacuo. The residual oil was treated with TFA (1 mL) at rt for 3 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.