Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(Br)cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2ccc(C(=O)NC3CCC(CCN4CCC(C(=O)c5ccc(F)cc5)CC4)CC3)nc2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
5-Bromo-pyridine-2-carboxylic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide (80 mg, 0.15 mmol) and 1-methylpiperazine (31 μl, 0.28 mmol) were dissolved in 2 ml dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9 mg, 0.016 mmol), cesium carbonate (76 mg, 0.23 mmol), water (1 μl, 0.078 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (8 mg, 0.008 mmol) were added and the reaction mixture was stirred for 16 hrs at 110° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The desired product was obtained as a light red solid (33 mg, 40%), MS: m/e=536.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[C:34](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)[C:14]([F:15])([F:17])[F:16])[N:8]2[CH3:34])=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(C)c2cc1Cl
Temperature: 25 °C

Procedure:
Ethyl 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (1.30 g, 2.63 mmol) (Synthesis Example 8, Stage 3) and potassium carbonate were initially charged in acetonitrile (39 ml) and admixed with iodomethane (561 mg, 3.95 mmol). The reaction mixture was heated under reflux overnight. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[O:9][CH:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[CH:4][CH:3]=1.[N:26]1([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:15]([CH2:14][NH:13][C:11](=[O:12])[CH:10]([O:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:34]=[CH:33][C:32]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:37][CH:36]=2)=[CH:3][CH:4]=1)[C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])#[N:16]
Reactant: OB(O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1nccs1)C(=O)NCC#N
Product: CC(C)CC(OC(c1ccc(-c2ccc(N3CCNCC3)cc2)cc1)c1nccs1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 21, 2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide from example 27, step 4 (225 mg, 0.53 mmol) was coupled with 4-piperazin-1-ylphenylboronic acid (141 mg, 0.58 mmol). The crude residue obtained was chromatographed on silica gel using 1% NH4OH and 9% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: OB(O)c1ccncc1
Product: Brc1ccc2ncc(-c3ccncc3)n2c1

Procedure:
The title compound, off-white solid (0.27 g, 45%), MS (ISP) m/z=274.4 [(M+H)+], mp 134° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available pyridine-4-ylboronic acid (0.27 g, 2.17 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH2:30])[CH3:29].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH:30][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(N)c1ccc(F)cc1-c1cc(F)ccc1F
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccc(F)cc2-c2cc(F)ccc2F)cc1
Yield: 87.8 %

Procedure:
The title compound was prepared from 4-methoxybenzenesulfonyl chloride (153 mg, 0.74 mmol), 1-(-2′,5′,5-trifluoro-1,1′-biphenyl-2-yl)ethylamine (177 mg, 0.70 mmol), and triethylamine (147 μL, 1.1 mmol) according to the procedure and in the same manner as described in Example 105, step c. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (259 mg, 91%) as a white solid;
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[F:11][C:12]1[C:13]([CH3:28])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=2)[C:15]([CH3:19])=[CH:16][C:17]=1O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:11][C:12]1[C:13]([CH3:28])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=2)[C:15]([CH3:19])=[CH:16][C:17]=1[O:5][C@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1
Reactant: Cc1cc(O)c(F)c(C)c1-c1cccc(CO)c1
Reactant: CS(=O)(=O)O[C@@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O[C@H]2CCOC2)c(F)c(C)c1-c1cccc(CO)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 50.7 %

Procedure:
The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (202 mg, 1.22 mmol), the crude 3-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 19b (200 mg, 0.81 mmol) and cesium carbonate (527 mg, 1.62 mmol) were dissolved in 5 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting mixture was mixed with 20 mL of water and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-(3′-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 19c (130 mg, yield 50.8%) as a colorless slime.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:25])=[C:6]([C@@H:14]2[CH2:18][CH2:17][N:16]([CH3:19])[C@H:15]2[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:7]([O:12][CH3:13])=[CH:8][C:9]=1[O:10][CH3:11])(=[O:3])[CH3:2].[Cl:26][C:27]1[C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:22]([O:21][CH2:20][C@H:15]1[C@H:14]([C:6]2[C:7]([O:12][CH3:13])=[CH:8][C:9]([O:10][CH3:11])=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=2[O:25][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][CH:29]=[N:28][C:27]=2[Cl:26])[CH2:18][CH2:17][N:16]1[CH3:19])(=[O:24])[CH3:23]
Reactant: O=C(O)c1cccnc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(O)c1C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(OC(=O)c2cccnc2Cl)c1C(C)=O

Procedure:
(+/−)-trans-Acetic acid 3-(3-acetyl-2-hydroxy-4,6-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-ylmethyl ester (1.65 g, 4.7 mmol) was reacted with 2-chloro-pyridine-3-carboxylic acid (2.44 g, 15.49 mmol) in the presence of dry pyridine (25 mL) and POCl3 (2.1 mL, 23.43 mmol) using the conditions described in example 52 to get trans-2-Chloro-nicotinic acid 2-(2-acetoxymethyl-1-methyl-pyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester. This was converted in situ to the title compound(66) using NaH (1.29 g, 26.86 mmol) in 1,4-dioxane (25 mL) as described in example 26.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1[S:8]([CH3:11])(=O)=O)#[N:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21](CS)=[CH:20][CH:19]=1.C(N(CC)CC)C>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1[S:8][CH2:11][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Reactant: COc1ccc(CS)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(C#N)c(SCc2ccc(OC)cc2)s1

Procedure:
To a stirred solution of 2.5 g (10 mmol) of methyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (Example 139, step (a)) in dry methanol (15 mL) was added p-methoxybenzylmercaptan (3.8 mL, 28 mmol) and triethylamine (1.4 mL, 10 mmol). This solution was refluxed for 15 min and cooled. The resulting solid was collected on a buchner funnel and washed with methanol (2×25 mL) to methyl 4-cyano-5-[(4-methoxyphenyl)methylthio]thiophene-2-carboxylate (2.84 g, 89%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26]Br.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(#N)C.C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:23][O:24][CH2:25][CH2:26][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: COCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: COCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.75 g, 17 mmol), K2CO3 (3 g, 21.7 mmol), bromoethyl methyl ether (2.84 g, 20.4 mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. The reaction was cooled. The inorganics were filtered and rinsed with DCM. The organic solution was concentrated down to an oil (7 g). Purification on a flash chromatography column (SiO2, 45 g; eluted with methanol/DCM) gave a light yellow oil as product (4 g, 87%). This oil was dissolved into ethanol and treated with a solution of fumaric acid (1.67 g) in ethanol (20 ml). White crystals (5.15 g) were collected, m.p.=157°-158° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].C([Li])CCCCC.[C:17]([N:24]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl-].[NH4+]>C(OCC)C>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]1([OH:29])[CH2:27][CH2:28][N:24]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1cccc(Br)c1F
Agent: [Cl-]
Agent: [Li]CCCCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)C1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of 1-bromo-2,3-difluorobenzene (8 g, 41.4 mmol) in dry diethyl ether (100 mL), under nitrogen, was added dropwise at −78° C., n-hexyllithium (2.3 M in hexane, 18 ml, 41.4 mmol). The mixture was stirred for 1 min after which a solution of 1-N-boc-3-pyrrolidone (7.66 g, 41.4 mmol) in dry diethyl ether (50 mL) was added dropwise. The resulting mixture was brought to ambient temperature and stirred for 2 h, aqueous saturated ammonium chloride solution (50 ml) was added and the mixture was extracted with ethylacetate (2×50 ml). The combined organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (8.12 g, 66%). MS m/z (rel. intensity, 70 eV) 243 (26), 198 (48), 141 (33), 127 (38), 57 (bp).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.[OH-].[K+]>O.C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:13][CH:12]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of 11.72 g (0.1 mole) of indole, 17.71 g (0.11 mole) of 4-chlorobenzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H2O, 2.5 g (2.5 mmoles) of PEG-1000 and 100 mL of toluene was stirred and heated at 55°-65° for 22 hours. After cooling to room temperature, 50 mL of H2O was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined organic phases were washed with 2N HCl (2×50 mL), H2O (2×50 mL), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 29 g of orange-brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 1:1 CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 12-19 were combined giving 23.11 g of crude product as a pink oil The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed as before. Fractions 20-30 were combined giving 20.33 g (84%) of 1-(4-chlorobenzyl)indole as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=O.[C:12](#[N:15])[CH:13]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[CH:13][C:12]#[N:15]
Reactant: C=CC#N
Reactant: Cc1ccc(C(=O)Cl)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: Cc1ccc(C=CC#N)cc1C
Yield: 31.8 %

Procedure:
0.448 g (2 millimols) of palladium acetate, 33.7 g (0.2 mol) of 3,4-dimethylbenzoyl chloride, 13.25 g (0.25 mol) of acrylonitrile and 37.06 g (0.2 mol) of tri-n-butylamine in 200 ml of p-xylene are stirred for 1.5 hours at 120° C. The mixture is then extracted by shaking with 200 ml of 2 N HCl, 200 ml of 2 N NaOH and 100 ml of water, after which it is dried for 15 minutes with 20 g of magnesium sulfate. The crude product is chromatographed on silica gel in methylene chloride, and is recrystallised from n-hexane. 10.0 g (32% of theory) of 3,4-dimethylcinnamonitrile are obtained as pale yellow crystals, melting point 93.9° C. Analysis for C11H11N: calculated C 84.04%, H 7.05%, N 8.91%; found C 83.65%, H 6.87%, N 9.03%.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([OH:14])=[O:13]>C(Cl)Cl.CO>[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([O:14][CH3:1])=[O:13]
Reactant: Nc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C

Procedure:
(Trimethylsilyl)diazomethane (6 mL, 2M solution in hexanes) was added to a solution of 3-amino-4-nitro-benzoic acid in CH2Cl2 (25 mL) and methanol (25 mL). Stirred at room temperature until bubbling ceased. Concentrated under vacuum to provide 1.2 g of desired product. MS (DCI) m/e 197 (M+H)+.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[N+](=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C(Cl)Cl>[C@H:1]12[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@H:8]1[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]2
Reactant: C1=CCCC=CCC1
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)OCC
Agent: CCOC(=O)C1(C(=O)OCC)[C@@H]2CC/C=C\CC[C@@H]21
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)[C@@H]2CCC=CCC[C@@H]21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1,5-cyclooctadiene (5.27 mL, 43.0 mmol) and Rh2(OAc)4 (100 mg, 0.23 mmol) in CH2Cl2 (5 mL) was added dropwise in 3 h a solution of diethyl diazomalonate (1.0 g, 5.37 mmol) in CH2Cl2 (5 mL). This solution was stirred for 24 h at rt. The CH2Cl2 was evaporated and the excess of cyclooctadiene was removed by filtration over a glass filter filled with silica (cluens: heptane). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EtOAc:heptane, 1:10) to afford IIa.8 (1.03 g, 72%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:29])([F:28])[C:11](=[O:27])[CH2:12][C:13]([CH3:26])([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([S:24][CH3:25])[CH:16]=1)[CH3:14].O>CS(C)=O>[CH3:26][C:13]([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([S:24][CH3:25])[CH:16]=1)([CH3:14])[CH2:12][C:11]1([C:10]([F:9])([F:28])[F:29])[CH2:2][O:27]1
Reactant: C[S+](C)(C)=O
Reactant: CSc1cc2c(c(C(C)(C)CC(=O)C(F)(F)F)c1)OCC2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc2c(c(C(C)(C)CC3(C(F)(F)F)CO3)c1)OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of trimethylsulfoxonium iodide (1.36 g, 6.1 mmol) in 7.7 mL of anhydrous DMSO was added sodium hydride (60% dispersion in mineral oil, 246 mg). The resulting solution was stirred at room temperature for 30 minutes and was then added dropwise to a solution of 1,1,1-trifluoro-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)pentan-2-one (1.63 g, 6.2 mmol) in 6.5 mL of anhydrous DMSO. After 2 hours, 100 mL of water was added and the resulting mixture was extracted with three 100 mL portions of diethyl ether. The combined organic phases were washed twice with water, aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, 1.64 g (95% yield) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([I:25])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH:31][CH3:30])=[O:19])=[CH:20][C:21]([I:25])=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:26]([F:27])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(I)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 3 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Example 1, Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (15 mL) was added dropwise methylamine (2.0 M solution in THF, 1.4 mL, 2.8 mmol) and the reaction mixture was stirred for 3 hours, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure and the residual solid was purified by chromatography on silica gel to afford 400 mg of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[C:4]([Cl:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([CH2:9][Br:11])=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)c(Br)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: Fc1cc(CBr)c(Cl)cc1Br
Temperature: 85 °C

Procedure:
A solution of 4-bromo-2-chloro-5-fluorotoluene (997 mg, 4.46 mmol), N-bromosuccinimide (837 mg, 4.70 mmol) and benzoyl peroxide (35 mg, 0.14 mmol) in carbon tetrachloride (20 mL) was heated to reflux at 85° C. for 18.5 hours under nitrogen. The reaction mixture was concentrated in vacuo to afford a cream solid residue. The residue was suspended in heptane (40 mL), filtered and the filtrate then concentrated in vacuo to afford the title compound a clear oil (1.35 g, 100%). The compound was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]3[S:19][C:18]([CH2:20][OH:21])=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.[H-].[Na+].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])=[C:4]([C:11]2[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]3[S:19][C:18]([CH2:20][O:21][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=4)(=[O:38])=[O:37])=[CH:17][C:15]=3[N:16]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cc2nc(-c3cc(F)cc4[nH]ccc34)nc(N3CCOCC3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCc2cc3nc(-c4cc(F)cc5c4ccn5S(=O)(=O)c4ccc(C)cc4)nc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
To a suspension of [2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-methanol (0.54 g, 1.41 mmol) in anhydrous THF (20 mL) and DMF (5 mL) was added sodium hydride (60% suspension in mineral oil, 0.34 g, 8.5 mmol). The resulting mixture was stirred at RT for 10 min, then p-toluenesulfonyl chloride (1.08 g, 5.66 mmol) was added and the reaction mixture was heated at 40° C. for 3 h. The resulting solution was partitioned between EtOAc and a saturated aqueous solution of ammonium chloride. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (0.60 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10](=[O:18])[CH2:9]2)=[CH:4][CH:3]=1.[OH:19][C:20]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:21]=1>>[C:20]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][C:10]2=[O:18])(=[O:19])[CH3:21]
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Reactant: O=C1CC(c2ccc(F)cc2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccc(F)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(4-fluorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one and being stirred for 2 h to obtain the title compound (99%).