Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[O:29][CH2:28][C@:13]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[N:14]=[C:15]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:16][C@H:17]([CH3:18])[C@@H:12]2[CH2:11]1)C1C=CC=CC=1.FC1C=C(F)C=CC=1[C@]12CO[C@@H](CO)C[C@H]1CSC(NC(=O)C1C=CC=CC=1)=N2>>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C@:13]12[CH2:28][O:29][C@@H:10]([CH2:9][OH:8])[CH2:11][C@H:12]1[C@@H:17]([CH3:18])[S:16][C:15]([NH:19][C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[N:14]2
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@@H]12
Agent: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12

Procedure:
The product was prepared from N-[(4R,4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C21) according to the general procedure for the synthesis of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a, 5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) in Preparation P1. In this case, the combined crude product from two similar reactions was triturated with dichloromethane rather than being purified by chromatography. The filtrate from the trituration was concentrated in vacuo, and a second crop of material was obtained via a second trituration with dichloromethane, affording the product in both cases as a white solid. Total yield: 23.12 g, 53.46 mmol, 79%. LCMS m/z 433.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.40-7.49 (m, 3H), 7.02-7.11 (m, 2H), 4.15 (br d, J=12 Hz, 1H), 3.91 (d, J=11.9 Hz, 1H), 3.71-3.78 (m, 1H), 3.60 (d, J=5.2 Hz, 2H), 3.19-3.28 (br m, 1H), 2.97-3.06 (br m, 1H), 1.74-1.82 (m, 1H), 1.49-1.62 (m, 1H), 1.26 (d, J=7.0 Hz, 3H).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:23]3[CH:24]=[CH:19][N:20]=[C:21]([NH:25][CH:26]4[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]4)[N:22]=3)=[CH:7][NH:6]2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2ccc(F)cc21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(F)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-6-fluoro-1H-indole (prepared by TBDMS protection of 6-fluoro-1H-indole) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 1.04 g (63%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[N:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)=[O:4].[CH3:15][CH2:16][Mg+].[Br-]>>[CH2:15]([C:11]1[CH:10]=[C:9]([CH3:12])[N:8]=[N:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH3:16]
Reactant: CC[Mg+]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)nn1
Agent: [Br-]
Product: CCc1cc(C)nnc1NC(=O)C(C)(C)C
Yield: 17.4 %

Procedure:
Using a procedure analogous to Example 17A, 2,2-dimethyl-N-(6-methyl-pyridazin-3-yl)-propionamide (4.18 g, 21.65 mmol) and 3.0 M solution of EtMgBr (36 mL, 108.29 mmol) give the title compound (0.83 g, 3.76 mmol, 17%). 1H NMR (CDCl3): δ 1.24 (t, J=7.5 Hz, 3H), 1.37 (s, 9H), 2.62 (q, J=7.5 Hz, 2H), 2.66 (s, 3H), 7.23 (s, 1H), 8.50 (s, 1H) ppm. ES-MS (m/z): calcd for C12H19N3O (M+H)+: 222.3. found: 222.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]2[N:14]=[C:15]([S:27][CH3:28])[C:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23](C)=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[C:12]2[N:11]=[C:10]([CH3:29])[CH:9]=1>CN(C=O)C>[C:20]1([S:17]([C:16]2[C:15]([S:27][CH3:28])=[N:14][N:13]3[C:8]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:9][C:10]([CH3:29])=[N:11][C:12]=23)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCNCC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
0.3 g (3.4 mmol) of piperazine in 10 ml of DMF was added to a solution of 0.62 g (1.7 mmol) of 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 6:1) and crystallization from EtOH yielded 0.30 g (42%) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 137-139°.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].C1(C)C=CC=CC=1.[C:13]([N:23]=[C:24]=[O:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C>C(OCC)(=O)C>[C:13]([NH:23][C:24]([N:4]1[CH2:5][CH:3]1[C:1]#[N:2])=[O:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CC1CN1
Reactant: O=C=NC(=O)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)C=Cc1ccccc1

Procedure:
A solution of 0.98 g. 2-cyanoaziridine in 20 ml. toluene is added dropwise, while stirring, at 20° to 30° C. to 2.5 g. cinnamoyl isocyanate dissolved in 20 ml. toluene. The resultant suspension is stirred for 1 hour at ambient temperature, then filtered off with suction and washed with toluene. The crystals obtained are triturated with anhydrous diethyl ether and dried for 1 hour at 50° C. in a vacuum to give 1.9 g. of crude product; m.p. 134°-136° C. This crude product is boiled with 50 ml. ethyl acetate for a short time, mixed with active charcoal and then filtered. The hot ethyl acetate filtrate is evaporated in a vacuum and the evaporation residue triturated with anhydrous diethyl ether. There is thus obtained 1.2 g. 1-(N-cinnamoyl-carbamoyl)-2-cyanoaziridine; m.p. 163°-164° C. The compound is practically insoluble in water but goes into solution upon the addition of excess 2 N aqueous sodium hydroxide solution.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C@H:6]1O)=[O:4].C(N(CC)CC)C.CS(Cl)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCC2(CCCCC2)[C@H]1O
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=CC2(CCCCC2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of trans-1-hydroxy-spiro[5.5]undecane-2-carboxylic acid methyl ester (2.74 g) obtained in Step 3 in chloroform (20 mL) was added triethylamine (2.02 mL). To the reaction mixture was added dropwise a solution of methanesulfonyl chloride (1.03 mL) in chloroform (5 mL) under ice-cooling, followed by stirring the reaction mixture at room temperature overnight. Then, after addition of water, the reaction mixture was washed therewith. The separated organic layer was dried and concentrated. To the residue were added tetrahydrofuran (30 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.62 mL), followed by heating the reaction mixture at 60° C. for 3 hours. After cooling down to room temperature, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:8) to give spiro[5.5]undec-1-ene-2-carboxylic acid methyl ester (2.075 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:6][CH:5]=1
Reactant: ClCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCl)cc1
Yield: 91.3 %

Procedure:
A mixture of 30.4 g (0.2 mole) of methyl-4-hydroxybenzoate, 68.6 g (0.4 mole) of 1-bromo-4-chlorobutane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 17 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to give an oil which crystallized. The solid was triturated with cold petroleum ether (30°-60° C.), collected by filtration, and dried to yield 44.3 g (92%) of title compound as a white solid. An analytical sample, mp 28.5°-29° C., was prepared from petroleum ether (30°-60° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1F.C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][NH:27][CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[N:27]([CH2:26][CH2:25][CH2:24][N:23]([CH3:29])[CH3:22])[CH3:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CNCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCCN(C)c1c(N)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A heterogeneous mixture of 1-chloro-2-fluoro-3-nitro-5-(trifluoromethyl)benzene (1.25 mL, 8.2 mmol), K2CO3 (3.44 g, 24.6 mmol), N1,N1,N3-trimethylpropane-1,3-diamine (1.26 mL, 8.61 mmol) and THF were allowed to stir at room temperature for 45 min. The THF was removed under reduced pressure and reconstituted in EtOAc (50 ml). The organic layer was washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated to an oil. The concentrated oil was taken up in EtOH (20 ml) to which Raney nickel (2.5 g wet, washed) was added. The reduction was monitored and after 1 h, another portion of Raney nickel (3.8 g, wet, washed) was added. The reaction was allowed to stir for an additional 30 min., and filtered through Celite, washed with EtOH (10 ml) and concentrated. The crude residue was purified via flash chromatography (silica gel, gradient elution 0 to 25% MeOH in CH2Cl2) to afford 6-chloro-N1-(3-(dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine as a yellow oil. MS m/z=310.1 [M+H]+. Calc'd for C13H19ClF3N3: 309.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[N+:27]([C:30]1[CH:31]=[C:32]([CH2:36][C:37](O)=[O:38])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>C(Cl)Cl.O1CCCC1>[N+:27]([C:30]1[CH:31]=[C:32]([CH2:36][C:37]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)Cc2cccc([N+](=O)[O-])c2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
tert-Butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) was dissolved in methylene chloride (4 mL) and then thionyl chloride (2.0 mL, 27 mmol) was added. The mixture was heated at 80° C. for 1 h. The solvent was removed under vacuum. Tetrahydrofuran (20 mL), triethylamine (2.3 mL, 17 mmol) and (3-nitrophenyl)acetic acid (0.87 g, 4.8 mmol) were then added and the mixture was stirred at rt for 1 h. The solvent was removed under vacuum and then EtOAc and water were added. The aqueous phase was extracted again with EtOAc. The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a white powder (1.70 g, 95%). LCMS for C19H21N3O5 (M-tBu+H)+: m/z=316.0.
Reaction SMILES: [F:1][C:2]1[C:3]([O:10][CH2:11][Si](C)(C)C)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F-].[Cs+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[F:1][C:2]1[C:3]2[O:10][CH2:11][CH:5]([OH:6])[C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)COc1c(F)cccc1C=O
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: OC1COc2c(F)cccc21
Temperature: 95 °C
Yield: 100.1 %

Procedure:
A mixture of 3-fluoro-2-((trimethylsilyl)methoxy)benzaldehyde (6.75 g, 29.8 mmol) and CsF (13.73 g, 90 mmol) in DMF (88 mL) were heated in 95° C. oil bath for 3 days. At the conclusion of this period, the reaction was analyzed by HPLC, which showed the starting material had disappeared. The reaction mixture was cooled to rt, diluted with aqueous NaHCO3 and extracted with Et2O (3×15 mL), followed by EtOAc (3×15 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried (MgSO4), and concentrated to afford Compound 1B as a brown oil (4.6 g). The crude product was used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:8]([Br:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Br:9])[C:2]=2[Br:1])=[O:19])=[CH:21][CH:22]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(Br)c1Br
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(Br)c2Br)cc1

Procedure:
The amide was prepared according to Example 18 from 2,3-dibromoaniline, 4-tert-butylbenzoyl chloride and diisopropylethylamine in dioxane. MS (ESI) m/z 408; HPLC Method B, purity 80.6% at 210-370 nm, 11.4 min.; 74.9% at 240 nm, 11.4 min.; HRMS: calcd for C17H17Br2NO+H+, 409.97496; found (ESI, [M+H]+), 409.9775.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O
Yield: 101.4 %

Procedure:
A solution of diethyl[4-(2,6-dichlorobenzyloxy)benzyl]malonate (3.02 g, 7.1 mmol) in ethanol (70 mL) with potassium hydroxide (0.48 g, 7.4 mmol) was stirred at room temperature for 18 h. The reaction mixture was diluted with water (100 mL) then concentrated to half the original volume in vacuo. The resulting aqueous solution was washed with ether then acidified with 3N HCl and the product extracted into ethyl acetate. The organic extract was washed with water then brine and dried (Na2SO4). Removal of solvent in vacuo afforded the title compound (2.86 g, 100%)
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.C(OCC)(=O)C>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]3[N:1]=[CH:2][CH:3]=[C:4]3[CH2:5]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccnn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid, m.p. 227°-229° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)([OH:3])=[O:2].FC(F)(F)C(O)=O.[N+:22]([O-])([OH:24])=[O:23]>>[C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: O=C(O)CCC1CCc2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-carboxyethylindane (28.8 g, 0.15 mol) and trifluoroacetic acid (300 mL) was cooled in an ice bath and then treated with fuming nitric acid (50 mL). The reaction mixture was slowly warmed to room temperature and allowed to stir for 18 h. After removing the solvent, the residue was dissolved in an either:water mixture. The ether layer was separated and washed with water, and then saturated NaCl, and dried over magnesium sulfate. The filtrate was evaporated to give a dark syrup (34.3 gm, 3:1 ratio of isomers).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-fluoro-4-(trifluoromethyl)benzoic acid (CAS RN 115754-21-7) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (20%). MS (ESI): m/z=389.13 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])[CH3:26])#[N:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])[N:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])[CH3:26])#[N:24]
Reactant: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4ccccc4)c3)c2cc1OC
Yield: 40.6 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (104 mg, 0.3 mmol) described in Example 308A to afford 1-(3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (68.87 mg, 40%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.74 (s, 6H), 4.04 (s, 6H), 6.58 (s, 1H), 7.26-7.86 (m, 10H), 8.63-8.69 (m, 2H), 9.28 (s, 1H); LC-MS (ESI) m/z 609 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>CC(O)=O>[Br:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:18][CH:19]=1)[NH:20][C:2]1[CH2:3][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:6][C:7]2=1
Reactant: CC(=O)NC1CCCC(=O)C1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)NC1CCc2c([nH]c3ccc(Br)cc23)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 0.05 mol of N-(3-oxocyclohexyl)acetamide in 100 ml of glacial HOAc was stirred and heated at 80° C. while adding during 15-30 minutes a warm solution of 0.05 mol of 4-bromophenylhydrazine hydrochloride in 300 ml of glacial HOAc. After an additional 3 hr at 85°, most of the HOAc was evaporated. The residue was triturated with H2O, until solid, the resulting solid was filtered, and recrystallized from ethanol to give the title compound, mp 210°-211°.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:26][C:27]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=4[C:29]([NH2:31])=[O:30])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2].[CH3:41]N.CO.C[O-].[Na+]>C1COCC1>[CH2:39]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:26][C:27]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=4[C:29]([NH:31][CH3:41])=[O:30])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:40]
Reactant: CN
Reactant: CCN(CC)CC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(=O)NC)c4ccnc-4[nH]3)cc21
Reaction time: 48 h

Procedure:
The remaining half of the reaction mixture from the preparation of 2-[(2-{[1-(N,N-diethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide was diluted with THF (100 mL) and a solution of methylamine (1M in THF, 10 mL). After 4 h the reaction mixture was concentrated, the resulting residue was sonicated in CH2Cl2 (10 mL) and filtered. The filtrate was purified by silica gel chromatography using 0-5% MeOH (containing 0.2% NH3)/CH2Cl2. The product was dissolved in THF (10 mL) and MeOH (20 mL) and treated with a solution of sodium methoxide (0.5M in MeOH, 4 mL, 2 mmol). The reaction mixture was stirred for 2 days, then concentrated onto Celite and purified by silica gel chromatography using 4% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[1-(N,N-diethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a yellow solid (60 mg, 30% for 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (t, J=7.15 Hz, 6H) 2.58 (q, J=6.72 Hz, 4H) 2.80 (d, J=4.77 Hz, 3H), 3.12 (t, J=8.43 Hz, 2H),3.77 (s, 3H), 4.24 (t, J=8.43 Hz, 2H), 6.27 (dd, J=3.30, 1.83 Hz, 1H), 6.76-7.03 (m, 3H), 7.26-7.39 (m, 1H), 7.57 (s, 1H), 8.36 (d, J=8.43 Hz, 1H), 8.54 (s, 1H), 8.62 (s, 1H), 10.16 (s, 1H), 11.26 (s, 1H), a CH2 signal with 2 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=561.27.