Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:34][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[N:25]([CH:22]1[CH2:23][CH2:24][N:19]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[CH2:20][CH2:21]1)[CH:26]=[CH:27]2
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc2c(ccn2C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2c(ccn2C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.07 mmol, 1.033 g), 1-(piperidin-4-yl)-1H-indol-5-amine (3.07 mmol, 0.66 g) and potassium carbonate (9.20 mmol, 1.271 g) were combined in acetonitrile (20 mL) and stirred at room temperature overnight. The reaction mixture was concentrated at reduced pressure. The resulting residue was taken up in dichloromethane and washed with water. The organic phase was dried over sodium sulfate and concentrated at reduced pressure. The solvent was removed and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 3% methanol/dichloromethane) to afford the title compound (332 mg).
Reaction SMILES: [Mg:1].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=[O:5]>>[CH2:2]([O:8][Mg:1])[CH3:3].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=[O:5]
Reactant: [Mg]
Agent: CCOC(=O)CC(=O)[O-]
Product: CCO[Mg]

Procedure:
Using the procedure of Step C of Example 6, 1.34 g of magnesium and 8.8g of ethyl malonate were reacted to obtain ethoxy magnesium of ethyl malonate to which was added over 30 minutes at room temperature a solution of 12.4 g of the product of Step B in 10 ml of dry toluene. The mixture was held at room temperature for 45 minutes and was then poured into 50 ml of 2N hydrochloric acid and 50 ml of ice. The mixture was extracted with ether and the extracts were washed with 5% sodium bicarbonate solution and then with water until the wash water pH was 6. The extracts were dried over magnesium sulfate, treated with activated carbon and evaporated to obtain 18 g of ethyl 2-[1-(2-trifluoromethylphenylamino)-2-methyl-prop-1-ylidene]-propanedioate in the form of a yellow oil which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Br[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)[C:20](=[O:24])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:28])[F:27]
Reactant: BrCc1cncnc1
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1Cc1cncnc1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2(1H)-pyrimidinone and 5-(bromomethyl)pyrimidine. LC-MS (ESI): m/z 503 [M+H]+; 3.55 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:12]1[C:11](=[O:14])[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)=[N:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(Cc2ccccc2)c1=O
Yield: 71 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and benzyl chloride were reacted to yield the title compound as yellow needles (yield: 71.0%).
Reaction SMILES: O.[OH-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:24]2[NH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:9]=[C:10]([O:22][CH3:23])[C:11]=1[O:12]S(C1C=CC=CC=1)(=O)=O.Cl>CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:24]2[NH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:9]=[C:10]([O:22][CH3:23])[C:11]=1[OH:12]
Reactant: COc1cc(-c2cc3ccccc3[nH]2)cc(OC)c1OS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(-c2cc3ccccc3[nH]2)cc(OC)c1O
Reaction time: 1 h
Yield: 80 %

Procedure:
Into a reactor were introduced 10 ml of water containing 4.8g of solid sodium hydroxide, 30 ml of methanol and 75.6g (0.02 mol) of 2-(3',5'-dimethoxy-4'-benzenesulphonyloxy-phenyl)-indole. The reaction medium was heated to 50°-55° C., was stirred for 1 hour and was poured into an aqueous solution of hydrochloric acid. The indole derivative was extracted with ether and the ethereal phase was washed with water to neutrality, dried, treated with charcoal and, finally concentrated under reduced pressure to give 2-(3',5'-dimethoxy-4'-hydroxy-phenyl)-indole which was recrystallized from a mixture of ethanol-acetone 60/40.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc([N+](=O)[O-])cc21
Product: CC1c2cc([N+](=O)[O-])ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Si]([C:15]([F:18])([F:17])[F:16])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[C:15]([F:18])([F:17])[F:16])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cc(Br)ccc1F)C(F)(F)F
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of 5-bromo-2-fluorobenzaldehyde (5.05 g, 24.9 mmol) in THF (200 mL) was cooled in a wet ice bath and treated dropwise with TMS-CF3 over five minutes. After stirring for 10 minutes, a solution of tetrabutylammonium fluoride (TBAF) in THF (1.0 mL, 1.0M) was added dropwise over 5 minutes. After stirring for 10 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with 1N HCl (50 mL) and allowed to stir for 2 hours. The mixture was diluted with 1N HCl (50 mL) and extracted with EtOAc (200 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 95:5) provided the title compound (3.28 g, 48%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 7.76 (dd, J=6.0, 2.0 Hz, 1H), 7.50 (ddd, J=8.5, 4.5, 2.5 Hz, 1H), 7.00 (overlapping dd, J=9.0, 9.0 Hz, 1H), 5.39 (overlapping dq, J=6.0, 6.0 Hz, 1H), 2.86 (d, J=5.5 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([CH:17]=O)=[CH:10][CH:9]=3)=O.[C:26]1([CH:32](P(=O)(OCC)OCC)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:47][C:48]([CH3:51])([O-])[CH3:49].[K+].CO>CN(C=O)C>[C:33]1([C:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:1][C:3]2[CH:4]=[CH:5][C:6]3[N:7]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[C:8]4[C:13]([S:14][C:15]=3[CH:16]=2)=[CH:12][C:11]([CH:17]=[C:47]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:15][CH:16]=2)[C:48]2[CH:51]=[CH:13][CH:8]=[CH:9][CH:49]=2)=[CH:10][CH:9]=4)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1ccc(N2c3ccc(C=O)cc3Sc3cc(C=O)ccc32)cc1
Reactant: CC(C)(C)[O-]
Reactant: CCOP(=O)(OCC)C(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(N2c3ccc(C=C(c4ccccc4)c4ccccc4)cc3Sc3cc(C=C(c4ccccc4)c4ccccc4)ccc32)cc1
Yield: 79 %

Procedure:
In 20 ml of DMF were dissolved 2.0 g (5.8 mmol) of 3,7-diformyl-10-p-tolylphenothiazine (2b) and 4.0 g (13.2 mmol) of diethyl diphenylmethylphosphonate (3a). Thereto was gradually added 1.5 g (13.4 mmol) of potassium t-butoxide. After the mixture was reacted overnight, 10 ml of methanol was added thereto. The crystals precipitated were taken out by filtration, dissolved in chloroform, purified by silica gel column chromatography (toluene), and then recrystallized from a chloroform/hexane mixed solvent to obtain 1.48 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[N:28]1([CH2:37][C:38](O)=[O:39])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:28]1([CH2:37][C:38]([O:10][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:12]=2)[CH2:8][C:7]2[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=2[Cl:1])=[O:39])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)Cn1ccc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cn1ccc2ccccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.615 g, 1.463 mmol), 2-(1H-indol-1-yl)acetic acid (0.282 g, 1.610 mmol), EDC (0.842 g, 4.39 mmol), and DMAP (0.268 g, 2.195 mmol) in DCM (20 ml) was stirred at room temperature overnight. The reaction was washed with 1N HCl, aqueous NaHCO3 and brine; the organic phase was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM/MeOH from 99/1 to 98/2) to afford (S)-4-(2-(2-(1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.615 g, 1.065 mmol, 72.8% yield). MS/ESI+ 577.2 [MH]+; [αD]=+5.500, c=0.44, DCM; 1H NMR (300 MHz, DMSO-d6) d ppm 8.52 (s, 2H), 7.48-7.63 (m, 1H), 7.27 (d, 1H), 7.13-7.19 (m, 2H), 7.10 (td, 1H), 7.00-7.05 (m, 1H), 6.99 (d, 1H), 6.92 (dd, 1H), 7.06 (t, 1H), 6.45 (dd, 1H), 6.02 (dd, 1H), 5.23 (d, 1H), 5.05 (d, 1H), 3.84 (d, 2H), 3.42 (dd, 1H), 3.20 (dd, 1H), 1.13-1.34 (m, 1H), 0.49-0.67 (m, 2H), 0.29-0.46 (m, 2H).
Reaction SMILES: C([O:8][C:9](=[O:21])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[CH:13]=[N:12]1)C1C=CC=CC=1>CO>[CH3:20][N:16]1[CH2:17][CH2:18][C:19]2[N:11]([CH2:10][C:9]([OH:21])=[O:8])[N:12]=[CH:13][C:14]=2[CH2:15]1
Reactant: CN1CCc2c(cnn2CC(=O)OCc2ccccc2)C1
Solvent: CO
Product: CN1CCc2c(cnn2CC(=O)O)C1

Procedure:
This compound was prepared using a method analogous to that of Example 14 step 14.2, (5-methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-acetic acid benzyl ester (described in Precursor for Example 215) replacing intermediate 14.1 and using MeOH instead of MeOH/AcOH. LC-MS (B): tR=0.16 min; [M+H]+: 196.27.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6]([S:8]([O:11][CH3:12])(=[O:10])=[O:9])=[CH2:7]>[I-].[Zn+2].[I-]>[CH:5]12[O:1][CH:2]([CH:6]([S:8]([O:11][CH3:12])(=[O:10])=[O:9])[CH2:7]1)[CH:3]=[CH:4]2
Reactant: C=CS(=O)(=O)OC
Reactant: c1ccoc1
Agent: [I-]
Agent: [Zn+2]
Product: COS(=O)(=O)C1CC2C=CC1O2
Reaction time: 48 h
Yield: 34 %

Procedure:
A four-neck flask having an internal capacity of 300 mL and fitted with a stirrer, a dropping funnel and a thermometer was charged with 150 g (2.20 mol) of furan and 15.0 g of zinc iodide, and 41.5 g (0.34 mol) of methyl vinylsulfonate was added dropwise from the dropping funnel at a temperature of 25 to 27° C. Stirring was continued at the same temperature for two days, and the reaction mixture was then transferred to a 1 L separating funnel. Following washing twice with 300 mL samples of water, the unreacted furan was removed by distillation under reduced pressure, yielding 22.0 g of methyl 7-oxabicyclo[2.2.1]hept-2-ene-5-sulfonate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]([NH2:26])=[S:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[S:25][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=3)[N:26]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)Nc1ccc(Cl)c(Cl)c1
Product: CS(=O)(=O)c1ccc(-c2csc(Nc3ccc(Cl)c(Cl)c3)n2)cc1
Yield: 78 %

Procedure:
(3,4-Dichloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amine was prepared in 78% yield using the procedure described in example 31 from 2-Bromo-1-(4-methanesulfonyl-phenyl)-ethanone and (3,4-Dichloro-phenyl)-thiourea. 1H NMR (300 MHz, DMSO-d6) δ 8.16-7.56 (m, 8H), 3.24 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1([CH:16]=[C:17]([F:20])[CH2:18][OH:19])[CH2:15][CH2:14]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:19][CH2:18][C:17]([F:20])=[CH:16][C:13]1([C:7]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=2[F:5])[CH2:14][CH2:15]1)(=[O:3])[CH3:2]
Reactant: OCC(F)=CC1(c2ccc(F)cc2F)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OCC(F)=CC1(c2ccc(F)cc2F)CC1
Yield: 92 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.46 ml), 1-(2,4-difluorophenyl)-1-(2-fluoro-3-hydroxyprop-1-enyl)cyclopropane (Example 15) (0.21 g), benzene (12 ml) and pyridine (0.09 ml) to yield the title compound (0.22 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[F:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([NH2:43])[CH:38]=1>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][C:39]3=[N:43][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(C(=O)Nc2c(F)cccc2F)c1
Reactant: Nc1cc(F)ccn1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1, step B) (0.6 g, 1.49 mmol) in DCM (15 mL) at rt under N2 was added NBS (0.278 g, 1.56 mmol). The reaction was stirred approximately 60 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (15 mL) and 4-fluoro-2-pyridinamine (0.5 g, 4.46 mmol) was added. The reaction was stirred under N2, heated to 75° C., and stirred for approximately 18 h, then cooled to rt. The reaction was diluted with EtOAc and half-saturated aqueous NaHCO3. The organic layer was separated and washed with brine. The combined aqueous layers were extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound of step B (0.391 g, 0.81 mmol, 55%) as a light yellow solid. MS (ESI): 480 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:17]([Cl:20])(=[O:19])[CH3:18]>>[ClH:20].[N:11]1([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: CC(=O)Cl
Product: CC(=O)NCCN1CCNCC1
Product: Cl

Procedure:
N-(2-piperazin-1-yl-ethyl)-acetamide hydrochloride was prepared from 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester and acetyl chloride in an analogous manner as described in example 22.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29])=[O:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: Cc1ccc(N)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 100 mL round-bottomed flask containing 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.44 ml, 2.9 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.48 ml, 3.4 mmol). After 10 min, 5-amino-2-methylbenzoic acid (0.400 g, 2.6 mmol) was added. The solution was stirred at rt overnight. After cooling, the crude reaction mixture was concentrated to remove excess NEt3 then diluted with CH2Cl2 and washed with 1 N HCl once, and brine & salt once then dried over Na2SO4 to afford 5-(2-fluoro-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid 32 as an off-white solid. MS m/z found: 342.1 (ESI, pos. ion).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12>O1CCCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
60% Sodium hydride in mineral oil (1.013 g, 25.34 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (8.5 g, 21.12 mmol) in tetrahydrofuran (150 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (6.18 g, 23.23 mmol) in tetrahydrofuran (20 mL) was added dropwise over a period of 5 minutes. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was quenched with 1M citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 100% ethyl acetate in isohexane to afford the product (7.15 g, 53.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH:17]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cc(C#N)ccc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)c1cc(C#N)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.6 g (16.3 mmol) of methyl (2-benzyloxy-5-cyano-phenyl)-acetate are dissolved in 10 ml of dimethylformamide and 1.9 g (17 mmol) of potassium tert. butoxide are added. Then 2 ml (16.8 mmol) of benzylbromide are added dropwise while cooling gently with ice and the mixture is then stirred for another two hours at ambient temperature. It is stirred with ice water and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. The crude product is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (0-7%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[Br:10])[NH2:6].[C:11](Cl)(Cl)=[O:12].Cl>ClC1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([N:6]=[C:11]=[O:12])[CH:7]=[CH:8][C:9]=1[Br:10]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C=Nc1ccc(Br)c(Cl)c1
Yield: 113.2 %

Procedure:
600 g of 3-chlor-4-bromaniline hydrochloride were suspended in 2500 ml chlorobenzene and the entire mixture was heated to 150°C to 160°C with vigorous stirring. About 1.25 kg of phosgene was introduced at this temperature; after about 10 to 16 hours all the hydrochloride had disappeared. The solvent was distilled off and the residue was rectified in vacuo. In this way 650 g of 3-chloro-4-bromo-phenylisocyanate, boiling at 122°C to 123°C at 12 mm Hg, were obtained.
Reaction SMILES: [CH3:1][O-].[Na+:3].[CH3:4][O:5][CH:6]=[O:7].CC[O:10][CH2:11][CH3:12]>>[O:7]=[C:6]1[O:5][CH2:4][CH2:1]/[C:12]/1=[CH:11]/[O-:10].[Na+:3]
Reactant: COC=O
Reactant: C[O-]
Reactant: CCOCC
Agent: [Na+]
Product: O=C1OCC/C1=C/[O-]
Reaction time: 8 h
Yield: 90 %

Procedure:
To a cooled suspension of 54.0 g. (1 mole) of sodium methoxide in a liter of dry ether, a mixture of 80 ml. (1.3 moles) of methylformate and 76 ml. (1 mole) of y-butyrolactone was added dropwise with stirring over a 2-h period. The stirring was continued at room temperature overnight. The reaction mixture was then cooled in an ice bath for 1 hr. to complete the separation of the cream-colored product which was then collected, washed with dry ether, and dried under vacuum to yield sodium (Z)-(2-oxodihydrofuran-3(2H)-ylidene)methanolate (123 g, 90%)