Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C(OC(Cl)=O)C(C)C.CN1CCOCC1.Cl.[CH3:46][NH:47][C:48](=[O:51])[CH2:49][NH2:50]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:50][CH2:49][C:48]([NH:47][CH3:46])=[O:51])=[O:14])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: CNC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CNC(=O)CNC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (1.0 g, 0.022 mol) in dimethylacetamide (10.0 mL) at −20° C. was added isobutylchloroformate (0.36 g, 0.0028 mol), followed by dropwise addition of N-methylmorpholine (0.30 g, 0.003 mol) and stirred for 10 min under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 20 min, cooled to 0° C., and added N-methylmorpholine (0.30 g, 0.003 mol) followed by the addition of N-methylglycine amide hydrochloride (0.35 g, 0.0028 mol) and DMAP (0.025 g). The reaction mixture was stirred at room temperature for 4 h, and concentrated in vacuo. The resulting the residue was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=535) were combined, and freeze-dried to give a white solid. This was dissolved in dichloromethane (25 mL), washed successively with 5% sodium bicarbonate (2×20 mL), water (2×20 mL), dried (Na2SO4), and concentrated to dryness to afford the racemic title compound (0.75 g, 65%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.96 (dd 1H, J=1.6 Hz, 8.0 Hz), 7.72 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.56 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.55 (abq, 2H), 3.99 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H), and 2.14 (s, 3H); ES-HRMS m/z 535.0792 (M+H calcd for C23H22N4O4F2 Br requires 535.0787). 19F NMR (CD3OD/400 MHz) −111.85 (m) and −115.91 (m).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[C:21](Br)=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:32]([C:36]#[CH:37])([CH3:35])([CH3:34])[CH3:33]>C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[C:21]([C:37]#[C:36][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cnc(Nc2nc(Cl)cn(Cc3ccccc3)c2=O)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnc(Nc2nc(Cl)cn(Cc3ccccc3)c2=O)c(C#C[Si](C)(C)C)c1
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
Compound 26 (2.0 g, 4.9 mmol), triphenylphosphine (52 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (173 mg, 0.25 mmol), triethylamine (1.03 mL, 7.4 mmol), and TMS-acetylene (1.05 mL, 7.4 mmol) were combined in THF (20 mL) at r.t. under nitrogen. After stirring 10 min, copper iodide (40 mg) was added, and the reaction stirred for 8 h. The reaction was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (2:1:2 hexanes/EtOAc/CH2Cl2) gave 2.0 g (96%) of the title compound as a pale yellow solid. MS (ES) [m+H] calc'd for C21H23ClN4OSi, 423, 425; found 423, 425.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]2[CH:43]=[C:42]([CH3:44])[C:36]3[N:37]([CH3:41])[C:38](=[O:40])[O:39][C:35]=3[CH:34]=2)=[O:32])[CH:28]=[C:27](Cl)[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN1C(=O)CCC1>[CH2:17]([O:24][C:25]1[N:26]=[C:27]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:28]=[C:29]([C:31]([C:33]2[CH:43]=[C:42]([CH3:44])[C:36]3[N:37]([CH3:41])[C:38](=[O:40])[O:39][C:35]=3[CH:34]=2)=[O:32])[CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(OCc3ccccc3)c2)cc2oc(=O)n(C)c12
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)c2cc(OCc3ccccc3)nc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
785 mg (3.60 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 500 mg (1.22 mmol) 6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one (mixture) were combined in 5 mL NMP and stirred overnight at 120° C. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and evaporated down. The residue was triturated with DIPE, suction filtered, washed with DIPE and dried.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:20]=1)(C)(C)C>C(Cl)(Cl)Cl>[CH3:26][C:23]1[O:22][C:21]([C:19]2[CH:20]=[C:15]([NH2:14])[CH:16]=[N:17][CH:18]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2cncc(NC(=O)OC(C)(C)C)c2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2cncc(N)c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.7 %

Procedure:
TFA (1 ml) was added to a chloroform solution (2 ml) containing tert-butyl(5-(5-methylfuran-2-yl)pyridin-3-yl)carbamate (61 mg) obtained in the 1st step, stirring at room temperature for 2 hours. The solvent was distilled away under reduced pressure, the obtained residue was dissolved in chloroform, and the resultant was washed with water and a saturated aqueous sodium hydrogen carbonate solution. Subsequently, the aqueous layers were combined, followed by extraction with chloroform (×2). The organic layers was combined and dried over anhydrous sodium sulfate. The solvent was distilled away from the obtained organic layers under reduced pressure, and a white solid of 5-(5-methylfuran-2-yl)pyridin-3-amine (46 mg) was thus obtained.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].C(N(CC)CC)C>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:26])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCCO
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCO)Oc1ccc(Oc2ccccc2)cc1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of the carbonate prepared in Example 1 (10.0 g, 28.4 mmol) in 75 mL of methylene chloride was added under nitrogen dropwise to a solution of 6-amino-1-hexanol (3.34 g, 28.4 mmol) and triethylamine (19.8 mL, 142 mmol) in 100 mL of methylene chloride at ice-bath temperature. The reaction was stirred at ice bath temperature for approximately eight hours and at room temperature overnight. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 8.1 g of a solid. Recrystallization of the solid from diisopropyl ether gave 6.55 g (70%) of the title compound as a white crystalline solid, mp 72°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:16])=[CH:14][CH:15]=1)=[O:9].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[C:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:11]=1)=[O:9]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: O=C(c1ccc(O)c(-c2ccccc2)c1)c1ccccc1Cl
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(C(=O)c3ccccc3Cl)cc2-c2ccccc2)cc1O
Yield: 68.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-chloro-phenyl)-(6-hydroxy-biphenyl-3-yl)-methanone (0.300 g, 0.972 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.436 g, 1.84 mmol) in THF. Purification by preparative HPLC (C18, eluting with CH3CN/H2O containing 0.1 % TFA), followed by crystallization from EtOAc/hexane gave 0.34 g (69%) of the title compound as a tan solid, mp 101-102° C. 1H NMR (DMSO-d6) δ 6.82 (d, 1H), 6.85 (dd, 1H), 7.14-7.16 (m, 2H), 7.27-7.33 (m, 3H), 7.52-7.54 (m, 1H), 7.58-7.65 (m, 5H), 7.71 (d, 1H), 7.81 (dd, 1H). IR (KBr) 3400, 3050, 1675, 1390 and 1190 cm-1. mass spectrum (EI) m/z 508 (M +). Anal. Calcd. for C26H17ClO7S 0.5H2O: C,60.29; H,3.50; N,0.00. Found: C,60.35; H,3.68; N,0.14.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][CH3:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCBr)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-2-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.8 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (400 mL), dried over MgSO4 and evaporated in vacuo to afford 17.4 g (99%) of 4-(2-bromoethoxy)-2-methoxybenzaldehyde, M.p. 78-79° C.
Reaction SMILES: [Li].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.[CH3:18][C:19]([CH3:21])=[O:20].C(O)(=O)C>O1CCCC1>[CH3:18][C:19]([OH:20])([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH3:21]
Reactant: COc1cc(CCCBr)cc(OC)c1OC
Reactant: CC(C)=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(CCCC(C)(C)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.7 %

Procedure:
To anhydrous tetrahydrofuran (10 ml) stirred in an ice bath under nitrogen were added 104 mg (15 mmol) of lithium, 3.9 g (14 mmol) of 1-bromo-3-(3,4,5-trimethoxyphenyl)propane (1), and a solution of 0.95 ml (13 mmol) of acetone in tetrahydrofuran (10 ml). After the mixture was stirred for 17 hours at room temperature, a 2% aqueous solution of acetic acid (50 ml) chilled with ice was added to conduct extraction with diethyl ether. An organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil (4.1 g) was purified by column chromatography on silica gel, thereby obtaining 860 mg (yield: 24%) of 2-methyl-5-(3,4,5-trimethoxyphenyl)pentan-2-ol.
Reaction SMILES: CN(C([O:8]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]([CH3:54])[CH:32]([C:34]2[CH:35]=[C:36]([C:51](O)=[O:52])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][C:39]3=[O:50])[CH3:33])[CH:27]=[C:28]([F:30])[CH:29]=1.[CH2:55]([N:57]([CH:61](C)C)C(C)C)[CH3:56].CNC(O)C>CN(C=O)C>[F:30][C:28]1[CH:27]=[C:26]([N:31]([CH3:54])[CH:32]([C:34]2[CH:35]=[C:36]([C:51]([N:57]([CH2:55][CH2:56][OH:8])[CH3:61])=[O:52])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:40][C:39]3=[O:50])[CH3:33])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Agent: CNC(C)O
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(c1cc(C(=O)N(C)CCO)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
TBTU (108 mg, 0.34 mmol) was added in one portion to a stirred solution of 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (0.103 mL, 0.59 mmol) and 2-s (methylamino)ethanol (0.027 mL, 0.34 mmol) in DMF (1 mL). The resulting solution was stirred at RT for 2 hrs. The reaction mixture was filtered and purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (90 mg, 64%) as a off-white solid. Mass Spectrum: M+H+ 502. NMR Spectrum (DMSOd6 at 323° K): 1.58 (d, 3H), 2.65 (s, 3H), 3.01 (s, 3H), 3.23-3.40 (m, 5H), 3.4-3.71 (m, 7H), 4.74 (bs, 1H), 5.52 (s, 1H), 5.57 (q, 1H), 6.38 (t, 1H), 6.53 (d, 2H), 7.74 (bs, 1H), 7.93 (s, 1H).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([O:32]C)=[O:31])[CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([CH3:28])[CH:27]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:30]([OH:32])=[O:31])[CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([CH3:28])[CH:27]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cnc(N)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 100 mg (4.18 mmol) LiOH in 25 mL water was added to a solution of 1.27 g (2.64 mmol) of (R)-2-(6-amino-5-methyl-pyridin-3-yl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 30 mL THF and the reaction solution was stirred for 1 h at RT. The mixture was evaporated down i.vac., the residue was taken up in water, 2 M KHSO4 solution were added with stirring, the supernatant solution was decanted off, the residue was dried, stirred with THF and the product was filtered.
Reaction SMILES: [NH2:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].N1C=CC=CC=1.[Br:24][CH2:25][C:26](Br)=[O:27]>C(Cl)Cl.C(OCC)(=O)C>[Br:24][CH2:25][C:26]([NH:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5])=[O:27]
Reactant: O=C(Br)CBr
Reactant: Nc1c(Cl)cccc1C(=O)c1ccccc1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CBr)Nc1c(Cl)cccc1C(=O)c1ccccc1F
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a solution of 2-amino-3-chloro-2′-fluorobenzophenone (4.80 g) and pyridine (3.04 g) in methylene chloride (100 ml) was added dropwise bromoacetyl bromide (3.42 ml) under stirring and cooling in an ice-bath. After the addition was completed, the mixture was stirred at ambient temperature for 0.5 hour and refluxed for 0.5 hour. The mixture was allowed to stand to cool to ambient temperature and evaporated in vacuo to give a residue, which was dissolved in ethyl acetate and washed with water three times and brine successively. After drying over magnesium sulfate and treating with active carbon, the solvent was removed in vacuo to give a crystalline mass. Pulverization in diisopropyl ether and collection by filtration afforded 2-(bromoacetylamino)-3-chloro-2′-fluorobenzophenone (5.86 g, 82.4% yield) as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:5]=[CH:6][C:7]([O:9][CH2:24][CH3:25])=[O:8]
Reactant: O=C(O)C=Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
3-Chloro-4-cyclohexylcinnamic acid (20.0 g.; 0.075 moles) is allowed to reflux with 8-10 pieces of Orierite in absolute ethanol (20 ml) containing concentrated sulfuric acid (5 ml) for 21 hours. The cooled reaction mixture is diluted with chloroform and filtered hot. The filtrate is washed 3 times with water, once with 10% sodium bicarbonate and twice more with water. After drying over sodium sulfate, the solvent is removed to give ethyl 3-chloro-4-cyclohexylcinnamate.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C1COCC1.CCOC(C)=O>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:21][C:19]2[CH:18]=[CH:17][C:15]3[NH:16][C:12]([C:8]4[C:7]([NH:6][C:4](=[O:5])[C:3]5[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=5[F:27])=[CH:11][NH:10][N:9]=4)=[N:13][C:14]=3[CH:20]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3c2)CC1
Temperature: 25 °C
Yield: 111.6 %

Procedure:
To a mixture of 2,6-difluoro-N-[3-(5-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (50 mg, 0.14 mmol) in anhydrous THF (1.5 mL) stirring at ambient temperature was successively added 3 Å molecular sieves, piperazine-1-carboxylic acid tert-butyl ester (52 mg, 0.28 mmol) and sodium triacetoxy borohydride (90 mg, 0.42 mmol). The mixture was stirred for 4 h, MeOH (3 ml) added and then the mixture was reduced in vacuo. The residue was taken up in EtOAc, washed with brine, dried (MgSO4), reduced in vacuo and then purified through preparative LC/MS to give the title compound (84 mg) as a yellow oil. (LC/MS: Rt 2.22, [M+H]+ 538.15).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:50]=[CH:51][C:52]5[C:53](=[N:63][N:64]([CH2:66][CH3:67])[CH:65]=5)[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:50]=[CH:51][C:52]5[C:53](=[N:63][N:64]([CH2:66][CH3:67])[CH:65]=5)[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CCn1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CCn1cc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(2-ethyl-6-oxo-8-phenyl-2,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.5 mL), water (3.5 mL) and 1 M HCl (0.2 mL) and chromatographed on a 5 g C18 cartridge {gradient 30 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (30.3 mg, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.53 (br s, 3H), 7.74 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.49-7.38 (m, 7H), 7.32 (d, J=8.1 Hz, 2H), 4.58 (q, J=7.3 Hz, 2H), 2.62-2.49 (m, 4H), 2.23-2.13 (m, 1H), 1.86-1.75 (m, 1H), 1.55 (t, J=7.3 Hz, 3H). LCMS (Method E): RT=3.36 min, [M+H]+=436.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](=[O:19])[CH2:17]Br.Br>>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:17][C:16]([C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[O:13][CH3:12])=[O:19])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: COc1ccccc1C(=O)CBr
Agent: Br
Product: COc1ccccc1C(=O)Cn1cccc2c(C)c(C)nc1-2

Procedure:
The title compound was prepared on a 1 mmol scale from 2,3-dimethylpyrrolo[2,3-b]pyridine and o-methoxyphenacyl bromide in the same manner as described in example 27 yielding 244 mg (71%) pure hydrobromide as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[N+:20]([O-])=O)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[O-]S([O-])(=O)=O.[Mg+2].[CH2:29]([O-:31])[CH3:30].[CH2:32](Cl)Cl>CO>[OH:31][CH2:29][C:30]1[CH:32]=[N:1][C:2]2[CH:3]=[C:4]3[CH2:5][C:6]4([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]4=[O:15])[CH2:16][C:17]3=[CH:18][C:19]=2[N:20]=1
Reactant: ClCCl
Reactant: CC[O-]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C1Nc2ncccc2C12Cc1cc3ncc(CO)nc3cc1C2
Reaction time: 4 h

Procedure:
To a stirred solution of 5,6-diamino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (320 mg, 1.20 mmol, described in Intermediate 13) and MgSO4 (1.06 g, 8.81 mmol) in CH2Cl2 (15 mL) and CH3OH (15 mL) was added the ethanolate of hydroxypyruvic aldehyde trimer [Evans et al., J. Am. Chem. Soc. 1938, 60, 1628-1629] (320 mg, 1.0 mmol). After 4 h, more of the ethanolate of hydroxypyruvic aldehyde trimer (340 mg, 1.1 mmol) was added and the mixture was heated to reflux for 2 h. The reaction mixture was partitioned between brine (50 mL) and EtOAc (150 mL). The organic layer was removed and the aqueous layer was extracted further with EtOAc (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=319 (M+1).