Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[CH3:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:18][CH2:17]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CC1OCCC1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([CH2:12][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CC1CCCO1
Product: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
4-Carboxybenzaldehyde (9 g, 60 mmol, 1.0 eq.) and biphenyl-2-yl-carbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (21.2 g, 60 mmol, 1.0 eq.) were combined in MeTHF (115 mL). The mixture was stirred for 0.5 hours, forming a thick slurry. Additional MeTHF (50 mL) was added to form a free-flowing slurry. 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (18 g, 63 mmol, 1.1 eq., 97% pure) was added in two portions and the funnel rinsed with additional MeTHF (50 mL). The mixture was stirred at room temperature overnight. MeCN (50 mL) was added and the mixture was filtered. The solids were washed with MeTHF (30 mL). The filtrate and washes were combined and a saturated NaHCO3 solution (100 mL) was added and stirred for 10 minutes. The layers were separated and a saturated NaCl solution (100 mL) was added and stirred for 10 minutes. The layers were separated and the aqueous layer discarded. The resulting solution was concentrated under reduced pressure and held at room temperature for three days, then used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Br[C:16]([C:18]([F:21])([F:20])[F:19])=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>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.C1COCC1.O>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:16]([C:18]([F:21])([F:20])[F:19])=[CH2:17])[CH:5]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of 3-Trifluoromethoxy-benzeneboronic acid (2.5 g) in a 2:1 mixture THF/H2O (36 ml) was added 2-Bromo-3,3,3-trifluoro-propene (3.1 ml), potassium carbonate (3.35 g), then Bis(triphenylphosphine)palladium(II) dichloride (169 mg). The reaction mixture was stirred at 60° C. for 7 hours. The solution was allowed to cool to room temperature then filtered on a Celite pad. The filtrate was concentrated in vacuo and the residue was then dissolved with ethyl acetate, extracted with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to give 1-Trifluoromethoxy-3-(1-trifluoromethyl-vinyl)-benzene (1.23 g). 19F-NMR (CDCl3, 75 MHz): −57.87 ppm and −64.94 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11]N=C[CH:8]=2)[S:5][CH:6]=1.BrC1SC=C(Br)C=1.[N:20]1C=CC=C(B(O)O)[CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[N:20][CH:21]=[CH:11][CH:12]=2)[S:5][CH:6]=1
Reactant: Brc1csc(-c2ccncc2)c1
Reactant: OB(O)c1cccnc1
Agent: Brc1csc(Br)c1
Product: Brc1csc(-c2cccnc2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Example 15 for the preparation of 4-bromo-2-(4-pyridyl)thiophene from 2,4-dibromothiophene and pyridine-3-boronic acid. The sub-title compound (2.30 g) was obtained as a pale solid, m/z 240, 242 (MH+).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14]([NH:16][C@H:17]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:15])=[O:6].[CH:47]1[C:59]2[CH:58]([CH2:60][O:61][C:62]([N:64]([CH3:71])[C:65]([CH3:70])([C:67](O)=[O:68])[CH3:66])=[O:63])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:56]1[C:57]2[CH:58]([CH2:60][O:61][C:62]([N:64]([CH3:71])[C:65]([CH3:66])([C:67]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14]([NH:16][C@H:17]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[S:15])=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:68])[CH3:70])=[O:63])[C:59]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #82 (670 mg, ≦0.818 mmol, 1 eq.), dichloromethane (5 mL, 0.16 M), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N,2-dimethylalanine (304 mg, 0.896 mmol, 1.1 eq.), HATU (372 mg, 0.978 mmol, 1.2 eq.) and diisopropylethylamine (440 μL, 2.53 mmol, 3.1 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 30% acetone in heptane) to give #83 (556 mg, 69% over two steps). LC-MS: m/z 994.7 [M+H+], retention time=0.69 minutes; HPLC (Protocol C): retention time=9.333 minutes (purity >98%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.53 (br d, J=8 Hz) and 10.80 (br d, J=8 Hz), total 1H], 7.86-7.91 (m, 2H), [7.80 (d, J=3.3 Hz) and 7.82 (d, J=3.2 Hz), total 1H], [7.64 (d, J=3.2 Hz) and 7.68 (d, J=3.2 Hz), total 1H], 7.62-7.66 (m, 2H), 7.38-7.44 (m, 2H), 7.28-7.36 (m, 5H), 7.19-7.26 (m, 2H), 7.12-7.17 (m, 1H), [6.31 (ddd, J=11, 8, 4.5 Hz) and 6.44 (ddd, J=11, 8.5, 4.5 Hz), total 1H], [4.42 (dd, J=9, 8 Hz) and 4.48 (dd, J=8, 8 Hz), total 1H], 3.22 and 3.24 (2 s, total 3H), 3.13 and 3.17 (2 s, total 3H), 2.89 and 2.97 (2 br s, total 3H), 2.84 and 2.85 (2 s, total 3H), [1.13 (d, J=6.4 Hz) and 1.16 (d, J=6.4 Hz), total 3H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:37][CH2:36][C:35]2[C:34]3[CH:33]=[C:32]([Cl:38])[C:31]([Cl:39])=[CH:30][C:29]=3[N:28]([CH2:40][C:41](O)=[O:42])[C:27]=2[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[NH:1]([C:41](=[O:42])[CH2:40][N:28]1[C:29]2[CH:30]=[C:31]([Cl:39])[C:32]([Cl:38])=[CH:33][C:34]=2[C:35]2[CH2:36][CH2:37][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][CH2:26][C:27]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Reactant: Nc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3cc(Cl)c(Cl)cc23)CC1
Reaction time: 18 h
Yield: 51.2 %

Procedure:
DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over-Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (98:2) to give 0.12 g of impure product. Then, crystallization from EtOAc/heptane gave 91 mg (39%) of a white solid: mp 172.5° C.; IR (diffuse reflectance) 3288, 1699, 1661, 1602, 1550, 1498, 1472, 1442, 1421, 1367, 1309, 1298, 1268, 1252, 1162 cm−1; MS (CI) m/z 488 (M+H+), 390, 388, 354, 153, 152, 136, 95, 93, 52, 51; Anal. Calcd for C25H27Cl2N3O3: C, 61.48; H, 5.57; N, 8.60; found: C, 61.49; H, 5.67; N 8.51.
Reaction SMILES: Br[CH:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>C(#N)C>[N:16]1([CH:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: CCCCC(Br)C(=O)c1ccc(Cl)cc1
Solvent: CC#N
Product: CCCCC(C(=O)c1ccc(Cl)cc1)n1cncn1

Procedure:
2-Bromo-4'-chlorohexanophenone (0.02 mol), 1,2,4-triazole (0.10 mol) and acetonitrile (50 ml) were refluxed for 48 hours. The acetonitrile was removed in vacuo and the residue extracted with chloroform (150 ml), washed with water (5×100 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo to leave an oil which crystallised on trituration with petroleum ether (5×50 ml). Recrystallisation from petroleum ether gave 2-(1,2,4-triazol-1-yl)-2-n-butyl-4'-chloroacetophenone, m.p. 81°-83°.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC>C1COCC1>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C(=C\c1ccccc1)\c1ccccc1

Procedure:
In the foregoing epititanations of diphenylacetylene conducted in THF or hexane, parallel epititanations were conducted in the same manner but the hydrolytic workup in each case was performed with 3N DCl in D2O. In these experiments the cis-stilbene isolated was >98% dideuteriated at the vinylic carbon atoms (12).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].C([Li])CCC.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15]>CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCCCCl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)C#CCCCCCl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 6-chlorohex-1-yne (100 mL, 94.6 g, 0.82 mol) in anhydrous Et2O (500 mL) at −78° C., n-butyllithium (2.5 M in hexane, 360 mL, 0.90 mol) was added over 40 minutes. The resulting mixture was stirred for 30 minutes at −78° C. Chlorotrimethylsilane (125 mL, 1.0 mol) was then added. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (300 mL) at room temperature and extracted with Et2O (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the title compound (144 g, yield 93%). 1H NMR (DMSO-d6, 400 MHz): δ 3.65 (t, 2H), 2.25 (t, 2H), 1.82-1.75 (m, 2H), 1.58-1.51 (m, 2H), 0.12 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=O.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C=O)C>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[C:3]2[CH:4]=[C:5]3[C:9]([CH2:8][CH2:7][CH2:6]3)=[CH:10][C:2]=2[O:1][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccccc1C(=O)c1cc2c(cc1O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cc3c(cc2c1-c1ccccc1C)CCC3
Reaction time: 0.5 h

Procedure:
A solution of (6-hydroxy-2,3-dihydro-1H-inden-5-yl)(2-methylphenyl)methanone (2.0 g) in DMF (50 ml) was combined with sodium hydride (60%, in oil) (400 mg) with cooling in ice. After stirring at the same temperature for 30 minutes, the mixture was combined with ethyl bromoacetate (1 ml), and stirred for 1 hour. The reaction solution was combined with water and extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was dissolved in toluene (50 ml), and combined with DBU (2 ml). The reaction solution was heated under reflux overnight, and then combined with water, and extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by a column chromatography (packing: silica gel, eluent: ethyl acetate-hexane=1:3) to obtain a crude product of ethyl 3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]furan-2-carboxylate. The resultant crude product of ester was dissolved in a solvent mixture of THF (50 ml) and methanol (30 ml), combined with a 1 N solution of sodium hydroxide (30 ml), and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resultant residue was combined with water and extracted with ethyl acetate after acidifying with diluted hydrochloric acid. The extract was washed with water, and then dried over magnesium, and the solvent was distilled off under reduced pressure. The resultant residue was purified by recrystallization from ethyl acetate to obtain the title compound (0.9 g, yield: 39%) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][CH2:22][C@@:23]([CH3:28])([CH:25]1[CH2:27][CH2:26]1)[OH:24]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:22][C@@:23]([CH:25]1[CH2:27][CH2:26]1)([OH:24])[CH3:28])=[O:9]
Reactant: C[C@](O)(CN)C1CC1
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Product: C[C@](O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid and (R)-α-(aminomethyl)-α-methyl-cyclopropanemethanol as starting materials, MS (ISP) 462.9, 464.9 (M−H).
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[C:11]([Cl:18])[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Cl:18][C:11]1[C:10]2[C:9](=[O:19])[C:8]3[CH:7]=[CH:6][C:5]4[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=4[C:17]=3[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: C=CCc1c(O)ccc2c(=O)c3c(Cl)cccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1Cc2c(ccc3c(=O)c4c(Cl)cccc4oc23)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.3 %

Procedure:
A mixture of 4-allyl-8-chloro-3-hydroxy-9-oxo-9H-xanthene (15 g), m-chloroperbenzoic acid (14 g) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and left to stand overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and, to the stirred solution, a mixture of chromium trioxide (15 g), water (90 ml) and concentrated sulfuric acid (26 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 8.0 g of 7-chloro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 283°-286° C. This compound produced a mass spectrum having a molecular ion peak at m/e 316.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=1)(=[O:19])=[O:18].C(OCC)(=O)C>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:17]([N:20]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=1)[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:18])=[O:19]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cnccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1Cl
Temperature: -5 °C

Procedure:
2-(Trimethylsilyl)ethoxymethyl chloride (0.22 ml) was added dropwise over 5 minutes to a stirred solution of 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.306 g) and N,N-diisopropylethylaminc (0.21 ml) in dry DMF (1 ml) at -15° C. The resultant solution was allowed to warm to -5° C. over 40 minutes then ethyl acetate (30 ml) was added and the mixture was washed with 2M hydrochloric acid (30 ml), water (30 ml) and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 30-50% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.266 g) as an oil; 1H NMR (d6 -DMSO): -0.1 (s, 9 H), 0.7 (t, 2 H), 2.45 (s, 3 H), 3.6 (t, 2 H), 3.85 (s, 3 H), 5.2 (s, 2 H), 7.8 (d, 1 H), 8.0 (s, 1 H), 8.8 (d, 1 H), 9.1 (s, 1 H); mass spectrum (+ve FAB, DMSO/Glycerol): 445 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23][CH2:24]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:24][CH2:23][CH2:22][Cl:21])[C:6]=2[CH:12]=1
Reactant: ClCCCI
Reactant: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2CCCCl
Yield: 79.1 %

Procedure:
6,8-Dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2225a) (2.33 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2225b) (2.44 g, 79%). 1H NMR (CDCl3) δ 7.02 (s, 1H), 4.67 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2, 2H), 2.43 (s, 3H), 2.18-2.10 (m, 2H); 13C NMR (CDCl3) δ 163.7, 140.5, 130.3, 128.3, 127.6, 124.1, 113.5, 67.9, 42.2, 39.3, 30.0, 17.2.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[C:18]([OH:19])=[CH:17][N:16]=[C:15]2[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=[CH:22][C:14]=12>CN(C=O)C>[F:12][C:13]1[C:18]([O:19][CH2:2][CH2:3][O:4][CH3:5])=[CH:17][N:16]=[C:15]2[NH:20][CH:21]=[CH:22][C:14]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cnc2[nH]ccc2c1F
Temperature: 65 °C
Yield: 49.7 %

Procedure:
1-Bromo-2-methoxyethane (0.586 g, 4.21 mmol) and potassium carbonate (1.16 g, 8.43 mmol) to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (1.3 g, 4.21 mmol; Example 119, Step A) in DMF (13 mL). The reaction was heated to 65° C. in a sealed tube for 18 hours, cooled down and then filtered. The filtrate was concentrated and purified by reverse chromatography (SP4, 25M, water/ACN 90/10->0/100, 30CV) to yield 4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridine (440 mg, 49.7% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([O:20]C)=O.[CH3:22][C:23]1[CH:27]=[CH:26][N:25]([CH2:28][C:29](OCC)=[O:30])[N:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([C:18]([OH:20])=[C:28]([N:25]3[CH:26]=[CH:27][C:23]([CH3:22])=[N:24]3)[C:29](=[O:30])[NH:1]2)=[CH:4][C:5]=1[C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1N
Reactant: CCOC(=O)Cn1ccc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccn(-c2c(O)c3cc(-c4ccc(N(C)C)cc4)c(Cl)cc3[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
To a solution of methyl 4-amino-6-chloro-4′-(dimethylamino)-[1,1′-biphenyl]-3-carboxylate, (Intermediate 47) (416 mg, 1.365 mmol) and ethyl 2-(3-methyl-1H-pyrazol-1-yl)acetate (Alinda Chemical Ltd, 275 mg, 1.638 mmol) in THF (8.4 mL) stirred under nitrogen at room temperature was added KHMDS 1M/THF (4.09 mL, 4.09 mmol) The reaction mixture was stirred at room temperature for 20 min before being quenched with MeOH, evaporated in vacuo and taken up in water (10 mL). The aqueous layer was acidified to pH=6-7 and filtered. The precipitate obtained was washed with acetonitrile, then with diisopropyl ether and filtered to give the title compound 7-chloro-6-(4-(dimethylamino)phenyl)-4-hydroxy-3-(3-methyl-1H-pyrazol-1-yl)quinolin-2(1H)-one (415 mg, 73.2% yield) as a light yellow powder. LCMS: (M+H)+=395; Rt=2.68 min. HRMS: calculated for C21H20ClN4O2 (M+H)+: 395.1275. found: 395.1283.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: C1CNCCN1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCNCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and piperazine. LCMS (Method C): 539 (M+H)+, Retention time 7.4 minutes.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:1][C:2]2[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)=[CH:39][CH:38]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (464 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (767 mg, yield 75%) was obtained as colorless crystals from a fraction eluted with ethyl-acetate. The crystals were recrystallized from ethyl acetate-hexane. melting point: 113–114° C.