Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:11]2[CH2:16][CH2:15][C:14]3[N:17]=[C:18]([NH2:20])[S:19][C:13]=3[CH2:12]2)=[N:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:11]2[CH2:16][CH2:15][C:14]3[N:17]=[C:18]([NH:20][C:30](=[O:32])[CH3:31])[S:19][C:13]=3[CH2:12]2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ncc(N2CCc3nc(N)sc3C2)nc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ncc(N2CCc3nc(NC(C)=O)sc3C2)nc1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.2 %

Procedure:
As shown in step 9-vi of Scheme 9, to a solution of Compound 1032 (65.4 mg, 0.223 mmol) in DCM (2 mL) was added DIEA (200 μL, 1.148 mmol) and acetic anhydride (200 μL, 2.12 mmol). The reaction solution was stirred at room temperature for 150 min and the crude produce purified by medium pressure silica gel chromatography (10 to 80% EtOAc in Hexanes) to give N-(4,5,6,7-tetrahydro-5-(5,6-dimethoxypyrazin-2-yl)thiazolo[5,4-c]pyridin-2-yl)acetamide (Compound 14, 36.8 mg) as an off white solid, which was salted as its mono-mesylate salt to yield a beige solid: ESMS (M+H) 336.12; 1H NMR (300.0 MHz, DMSO-d6) δ 7.31 (s, 1H), 4.55 (s, 2H), 3.91 (m, 3H), 3.83 (m, 5H), 2.73 (t, J=5.4 Hz, 2H), 2.39 (d, J=0.6 Hz, 3H) and 2.12 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:3]([Cl:27])=[C:4]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].[O:35]=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>C1COCC1>[C:13]([O:12][C:11]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]1[C:3]([Cl:27])=[C:2]([C:36]2([OH:35])[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:39]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(Br)c2Cl)cc1
Agent: CC(C)[Mg+]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(C3(O)CN(C(=O)OC(C)(C)C)C3)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (Intermediate (500 mg, 1.107 mmol) in THF (2.5 ml) at 0° C. was added drop wise isopropylmagnesium lithium chloride (1.3 M in THF) (0.937 mL, 1.218 mmol) under nitrogen. After stirring at 0° C. for 30 min, removal of the cooling bath and stirred at room temperature for 30 min. The reaction mixture was cooled to −14° C. (NaCl-ice bath), to this was added drop wise a solution of tert-butyl 3-oxoazetidine-1-carboxylate (208 mg, 1.218 mmol) in THF (2 mL), and left stirring in the cooling bath for 2 h, during this time the temperature rose to −4° C. The reaction was quenched with sat, aqueous NH4Cl solution (5 ml), and diluted with EtOAc, washed with water, brine, and dried over Na2SO4. Solvent was removed. The crude residue was purified by ISCO (12 g) column chromatography, eluting with hexane containing 0 to 40% EtOAc to afford tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)-3-hydroxyazetidine-1-carboxylate (408 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([F:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 22.5 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (21 mg, 23% over 2 steps) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.36 (s, 1H), 8.27 (dd, J=8.8, 1.9 Hz, 1H), 8.24 (d, J=2.7 Hz, 2H), 8.06 (d, J=8.8 Hz, 1H), 7.90 (dd, J=9.4, 2.6 Hz, 1H), 7.27 (m, 2H), 7.08 (d, J=9.4 Hz, 1H), 4.16 (p, J=6.2 Hz, 1H), 4.05 (dd, J=11.9, 6.5 Hz, 1H), 3.88 (dt, J=10.8, 7.5 Hz, 1H), 3.79 (dt, J=10.5, 3.3 Hz, 2H), 2.81 (p, J=6.0 Hz, 1H), 2.61 (dq, J=13.3, 6.6 Hz, 1H), 2.33 (td, J=13.4, 5.3 Hz, 1H), 1.20 (m, 4H); ESI MS m/z 518 [C28H25ClFN5O2+H]+; HPLC 99.4% (AUC), tR=10.02 min.
Reaction SMILES: [N:1]#[C:2][NH2:3].[H-].[Na+].[Cl:6][C:7]1[C:16](Cl)=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:19]([O-:21])=[O:20])=[C:12]([F:18])[CH:13]=2)[N:8]=1>CN(C=O)C>[Cl:6][C:7]1[C:16](=[N:3][C:2]#[N:1])[NH:15][C:14]2[C:9](=[CH:10][C:11]([N+:19]([O-:21])=[O:20])=[C:12]([F:18])[CH:13]=2)[N:8]=1
Reactant: N#CN
Reactant: O=[N+]([O-])c1cc2nc(Cl)c(Cl)nc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN=c1[nH]c2cc(F)c([N+](=O)[O-])cc2nc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
To a solution of cyanamide 2.31 g in DMF 100 mL, was added sodium hydride (60% suspension in oil) 4.40 g under ice-cooling. The mixture was stirred at room temperature for 30 min, to which 2,3-dichloro-6-fluoro-7-nitroquinoxaline 13.10 g was added under ice-cooling, followed by raising slowly to room temperature. The resulting mixture was stirred at room temperature for 20 min, then which was poured into ice water containing 1N HCl 110 mL under stirring. The precipitation was collected by filtration and washed with water and i-PrOH to give the title compound 12.80 g.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCCC1.C(O)C>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH2:20][CH2:19]1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(C2c3ccccc3-c3[nH]c(=O)c(=O)[nH]c32)CC1
Reaction time: 20 h
Yield: 38.3 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (1.50 g, 6.39 mmol) was suspended in 15 ml of dry tetrahydrofuran, while cooling in an ice bath. N-Methylpiperazine (1.42 ml, 12.78 mmol) dissolved in 3 ml of dry tetrahydrofuran was added over 20 min, and the ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran and dried to give 2.42 g of a remanence, which was dissolved in 100 ml of boiling ethanol, and treated with 300 mg of activated carbon. The mixture was filtered and concentrated to 10 ml. The precipitate was filtered off, washed with ethanol and dried to give 0.65 g of the crude product. From the filtrate another crop of 0.57 g could be isolated. Recrystallization from 6M HCl afforded 0.73 g (30%) of the title compound as a dihydrochloride. M.p. 263°-265° C. 1H-NMR (DMSO-dd6, δ): 2.6 (m, 1H), 2.73 (s, 3H), 2.78-3.52 (m, 7H), 4.84 (s, 1H), 5.9-7.0 (broad, 2H), 7.2 (t, 1H), 7.35 (t, 1H), 7.48 (d, 1H), 7.58 (d, 1H), 10.92 (s, 1H), 11.76 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22]1([C:28]2[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:34]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:33]=4)=[O:35])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccnc(-c2ccccc2)n1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccnc(-c3ccccc3)n2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.9 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 2-phenylpyrimidine-4-carboxylic acid (99.5 mg, 0.50 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 48 h. The solution was filtered off and concentrated under vacuum. The residue was chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:1) and the solvent evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6methyl-1,1′-biphenyl-3-yl)-2-phenylpyrimidine-4-carboxamide (13 mg). NMR; δH CDCl3 9.98,(1H, s), 9.09,(1H, d), 8.50-8.47,(2H, m), 8.08,(1H, d), 7.86,(2H, d), 7.70,(1H, dd), 7.63,(1H, d), 7.56-7.54,(3H, m), 7.45,(2H, d), 7.33,(1H, d), 7.26,(1H, m), 3.36,(2H, m), 2.26,(3H, s), 1.09,(1H, m), 0.58,(2H, m), 0.30,(2H, m). LCMS: retention time 3.88 min, MH+463.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[N:11]=[CH:12][N:13]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)C=CC=CC=1.C([Li])CCC.CCCCCC.O=[CH:58][CH2:59][C@H:60]([NH:68][C:69]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70])[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62].[Cl-].[Na+]>O1CCCC1>[C:73]1([CH2:72][O:71][C:69]([NH:68][C@@H:60]([CH2:59]/[CH:58]=[CH:9]/[C:10]2[N:11]=[CH:12][N:13]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:14]=2)[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:70])[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CC=O)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](C/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
50.93 g (820 mmol) of triphenyl[[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]phosphonium chloride in solution in 333 ml of tetrahydrofuran are introduced, under argon, into a three-necked round-bottomed flask. 51.2 ml of a 1.6M solution of n-butyllithium in hexane (820 mmol) are added dropwise, at -70° C. After stirring for 30 minutes at -70° C., the reaction mixture is quickly poured into 270 ml of a 0.253M solution, cooled to -70° C., of 1,1-dimethylethyl (S)-4-oxo-2-[[(phenylmethoxy)carbonyl]amino]butanoate in tetrahydrofuran (683 mmol). The mixture is allowed to return to room temperature overnight. The mixture is hydrolysed with 280 ml of a saturated aqueous sodium chloride solution. The aqueous phase is separated from the organic phase and extracted with 2 times 140 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated to dryness. Purification is carried out by chromatography on a column of silica gel, the eluent being a hexane/ethyl acetate gradient.
Reaction SMILES: [CH3:1][I:2].[C:3]([Si:7]([CH3:23])([CH3:22])[O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[O:16])[CH2:11][CH2:10]1)([CH3:6])([CH3:5])[CH3:4]>C(#N)C>[I-:2].[C:3]([Si:7]([CH3:23])([CH3:22])[O:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([N:17]2[CH:21]=[CH:20][N+:19]([CH3:1])=[CH:18]2)=[O:16])[CH2:13][CH2:14]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)n2ccnc2)CC1
Reactant: CI
Solvent: CC#N
Product: C[n+]1ccn(C(=O)N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
Methyl iodide (113.5 g, 0.80 mol) was added to a stirred solution of [4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-imidazol-1-yl-methanone (61.9 g, 0.20 mol) in acetonitrile (400 mL). After stirring overnight at room temperature the solvent was evaporated in vacuo. The residue was washed with ethyl acetate:heptane and dried in a vacuum oven at 45° C., yielding the title compound (60.92 g, 68% yield over three steps) as a white solid
Reaction SMILES: [Cl:1][C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:10]([CH3:12])=[CH:11][C:3]=12.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:10]([CH3:12])=[C:11]([C:28](=[O:29])[CH2:27][Cl:26])[C:3]=12
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)c(-n2c(C)cc3c2=NC(C)NC=3Cl)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(-n2c(C)c(C(=O)CCl)c3c2=NC(C)NC=3Cl)c(C)c1

Procedure:
Compound (6) (11.2 g, 37.4 mmol) was added to a chloroform solution (150 ml) or 20 equivalents of aluminum chloride and 25 equivalents of chloracetyl chloride. The solution was heated at reflux for 16 hrs. The organic layer was departed and the water layer extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to yield compound (7).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Cl[C:6]([O:8][CH3:9])=[O:7].C(#N)C.[CH2:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1)[CH2:14][CH2:15][CH3:16]>O>[CH3:9][O:8][C:6]([NH:3][C:2]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][C:19]=1[N+:24]([O-:26])=[O:25])=[S:1])=[O:7]
Reactant: N#C[S-]
Reactant: COC(=O)Cl
Reactant: CCCCc1ccc(N)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Temperature: 15 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Dry potassium thiocyanate (42.8 g; 0.44 mole), methyl chloroformate (37.8 g; 0.40 mole) and dry acetonitrile (130 ml) were mixed with stirring at laboratory temperature and stirring was continued for 1 hour at 35°-45° C. The mixture was then cooled in an ice bath to 15° C. and 4-n-butyl-2-nitroaniline (38.8 g; 0.2 mole) was added in portions with stirring during 15 minutes, the temperature of the stirred reaction mixture being maintained between 15° and 18° C. during the addition. When the addition was complete the mixture was stirred at 15° C. for 2 hours, poured into water (1 litre), and the yellow solid which separated was filtered off and washed with water. This crude product was recrystallised from ethanol to give 1-methoxycarbonyl-3-(4-n-butyl-2-nitrophenyl)thiourea (47.8 g), m.p. 164°-165° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:7]1([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[CH2:8]1)[CH2:6][CH:5]2O.[CH3:28][N:29]=[C:30]=[O:31].C(O)(=O)/C=C/C([O-])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:7]1([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[CH2:8]1)[CH2:6][CH:5]2[C:30](=[O:31])[NH:29][CH3:28]
Reactant: CN=C=O
Reactant: O=C(CCCN1CCC2(CC(O)c3cc(Cl)ccc32)C1)c1ccc(F)cc1
Agent: O=C([O-])/C=C/C(=O)O
Solvent: ClC(Cl)Cl
Product: CNC(=O)C1CC2(CCN(CCCC(=O)c3ccc(F)cc3)C2)c2ccc(Cl)cc21

Procedure:
4-(5-Chloro-3-hydroxyspiro[indan-1,3'-pyrrolidin]-1'-yl)-p-fluorobutyrophenone is reacted with methyl isocyanate in chloroform in a manner analogous to that described in Example 19. Reaction time 24 hours at the boil. The hydrogen fumarate of the title compound has a M.P. of 151°-153° (from ethanol/ether).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][C@H:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(OC2C=CC(O[C@H](C)C(O)=O)=CC=2)=CC=1.C(Cl)(=O)C(Cl)=O.[Na].[C:54]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:55][C:56]([CH3:58])=[O:57]>CCOCC.CN(C=O)C>[C:56]([C@H:55]([C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17])[C:54]([O:60][CH2:61][CH3:62])=[O:59])(=[O:57])[CH3:58]
Reactant: CCOC(=O)CC(C)=O
Reactant: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Agent: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C(C)=O)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following the procedure of Example 12, (R)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid chloride is prepared from (R)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid (1.0 g, 3.06 mmol) and oxalyl chloride (0.6 ml) in ether (10 ml) and DMF (2 drops). The acid chloride is then reacted with the sodium salt of ethyl acetoacetate (0.084 g of sodium and 0.480 g of ethyl acetoacetate) to give ethyl (R)-2-acetyl-4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (XVIII; Q1 is CH, Y is hydrogen, Z is trifluoromethyl and R3 is ethyl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:23][O:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:17]=[C:18]([C:30]5[C:25]([O:24][CH3:23])=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:19]=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ncccc1-c1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 110 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide (36 mg, 0.10 mmol) was dissolved in 1 mL of ethanol containing 0.12 mL of a 2 M aqueous solution of potassium carbonate, 2-methoxypyridin-3-ylboronic acid (18 mg, 0.12 mmol) and 6 mg of Fibre-Cat 1007. The reaction mixture was then heated to 110° C. for 10 minutes in a microwave reactor. The resulting material was cooled to room temperature, filtered, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product. ESI-MS m/z calc. 389.1. found 390.1 (M+1)+. Retention time 3.09 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]#[C:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1.I[C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(=O)([O-])[O-].[Na+].[Na+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-2](Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:27][N:2]([CH3:1])[C:3]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:32]3[C:30](=[CH:29][CH:35]=[CH:34][CH:33]=3)[NH:31][C:14]=2[Si:15]([CH2:18][CH3:19])([CH2:20][CH3:21])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1
Reactant: Nc1ccccc1I
Reactant: CC[Si](C#CCCCC1(O)CCC(c2cccs2)(N(C)C)CC1)(CC)CC
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-2](Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC[Si](CC)(CC)c1[nH]c2ccccc2c1CCCC1(O)CCC(c2cccs2)(N(C)C)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-dimethylamino-4-(thiophen-2-yl)-1-(5-(triethylsilyl)pent-4-inyl)cyclohexanol (3.00 g, 7.4 mmol), 2-iodoaniline (1.94 g, 8.9 mmol), [1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride (PEPPSI, 503 mg, 0.74 mmol) and sodium carbonate (3.92 g, 37 mmol) was evacuated for 30 min (oil pump). It was then flushed with argon and absolute N,N-dimethylformamide (10 mL, previously flushed for 1 h with argon) was added by syringe via a Schlenk tube. The reaction mixture was stirred for 18 h at 100° C. and changed colour to dark brown during this. The reaction mixture was then concentrated to low volume in a vacuum, the residue taken up several times in toluol (3×30 mL) and concentrated to low volume again in each case. The residue was distributed between water and ethyl acetate (100 mL each), the phases were separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with 1 M sodium thiosulphate solution and saturated sodium chloride solution (50 mL each), dried with sodium sulphate and concentrated to low volume in a vacuum. The residue (4.40 g) was purified by means of flash chromatography (200 g, 20×5.7 cm) with dichloromethane/methanol (95:5).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH:39]1[CH2:42][CH:41]([C:43]#[N:44])[CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:39]3[CH2:42][CH:41]([C:43]#[N:44])[CH2:40]3)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: N#CC1CNC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CC(C#N)C3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, azetidine-3-carbonitrile was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give 1-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-yl]-azetidine-3-carbonitrile. MS: (ES+): 454
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:34])=[C:29]([CH:33]=1)[C:30](Cl)=[O:31]>>[NH:17]1[C:11]2[C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[C:25]([F:24])[CH:26]=[CH:27][C:28]=4[CH3:34])=[CH:3][CH:4]=3)=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=[N:16]1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ncccc32)cc1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ncccc32)cc1

Procedure:
As described for Example 2, 2 mmol of 6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]pyrido-[3,2-b]azepine is reacted with 2.2 mmol of 5-fluoro-2-methylbenzoyl chloride to give the product as a solid.