Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:52]=[CH:51][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([NH:42][CH:43]5[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]5)=[O:41])=[CH:51][CH:52]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CCN1CCC(NC(=O)c2ccc(N)cc2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Yield: 70.8 %

Procedure:
A mixture of 0.10 g (0.30 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.086 g (0.45 mmole) of toluenesulfonic acid monohydrate, 0.075 g (0.30 mmole) of 4-amino-N-(1-ethyl-piperidin-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 170 degrees in a microwave reactor for 2 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 0.115 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-benzamide (I-261).
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([CH2:24][CH3:25])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=O)[CH3:2].Cl.[NH2:27][OH:28].Cl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([CH2:24][CH3:25])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[N:27][OH:28])[CH3:2]
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a mixture of 0.75 g of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde and 10 ml of pyridine was added 0.15 g of hydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.67 g (yield, 75%) of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde oxime, nD24.5 1.5278.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3].F[C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1>>[CH2:1]([C:4]1[N:5]([C:10]2[CH:20]=[CH:19][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CCCc1ncc[nH]1
Product: CCCc1nccn1-c1ccc(CO)cc1

Procedure:
Prepared from 2-propylimidazol and ethyl 4-fluorobenzoate.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12](=[O:15])(=[O:14])[NH2:13])[C:8](=[O:16])[CH2:7][CH2:6]2.BrBr.OS([O-])=O.[Na+]>C(O)(=O)C>[Br:1][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:11]([S:12](=[O:14])(=[O:15])[NH2:13])=[C:3]([Cl:2])[CH:4]=2)[C:8]1=[O:16]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)CCC2=O
Reactant: Br
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2c(cc1Cl)CC(Br)C2=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
0.1 Milliliter of 48% aqueus HBr is added to a suspension of 52 g (0.21 mole) of 5-chloro-6-sulfamoyl-1-indanone in 530 ml of glacial acetic acid. Subsequently a solution of 34.0 g (0.21 mole) of bromine in 160 ml of glacial acetic acid is added dropwise. The mixture is stirred for another 1.5 hours, and is then poured into a solution of 4.5 g of NaHSO3 in 2 of ice water. The 2-bromo-5-chloro-6sulfamoyl-1-indanone which crystallizes after stirring for some time is filtered off with suction and is washed with water.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:14][CH2:15][CH3:16])[CH2:3][CH:4]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[C:5]#[CH:6].C(BC(C(C)C)C)(C(C)C)C.[Br-:29]>C(Cl)(Cl)(Cl)Cl>[Br:29]/[CH:6]=[CH:5]/[CH:4]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH2:3][C:2]([CH3:17])([CH3:1])[CH2:14][CH2:15][CH3:16]
Reactant: [Br-]
Reactant: C#CC(CC(C)(C)CCC)OC1CCCCO1
Agent: CC(C)C(C)BC(C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(C)(C)CC(/C=C/Br)OC1CCCCO1

Procedure:
Treatment of 7.15 g. (30 moles) of 5,5-dimethyl-3-tetrahydropyranyloxy-1-octyne (Example 999) with 33 moles of disiamylborane in carbon tetrachloride followed by 30 moles of bromide in carbon tetrachloride, refluxing the resulting mixture, and isolation by chromatography on silica gel, all as described in Example 1173 gives the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[CH:6]([NH:19][C:20](=[O:31])[C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])[C:5]1=[O:32].Cl>C(#N)C>[NH2:23][C@@H:21]([CH3:22])[C:20]([NH:19][C@H:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=2[N:4]([CH2:3][CH2:2][OH:1])[C:5]1=[O:32])=[O:31]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N(CCO)c2ncccc2-c2ccccc21
Agent: Cl
Solvent: CC#N
Product: C[C@H](N)C(=O)N[C@@H]1C(=O)N(CCO)c2ncccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.4 %

Procedure:
Combine tert-butyl N-[(1S)-2-[[5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]carbamate (54.0 g, 0.12 mol) and acetonitrile (212.7 mL) under a nitrogen atmosphere. Add hydrochloric acid (317.5 mL, 4N, 1.27 mol) drop-wise to maintain the internal temperature below 30° C., and stir the reaction mixture for 16-18 hours at 20-30° C. Add water (324.0 mL) and dichloromethane (430 mL) and separate the layers. Discard the organic layer and to the aqueous phase add dichloromethane (645 mL) and adjust the pH to approximately 10 using aqueous sodium hydroxide (20%, 252 mL). Separate the layers, extract the aqueous layer with additional dichloromethane (2×430 mL), and combine the organic phases. Concentrate the organic under reduced pressure below 45° C. to an approximate volume of 130-150 mL, and add tetrahydrofuran (322 mL). Concentrate the solution under reduced pressure below 45° C. to an approximate volume of 200-220 mL, and add additional tetrahydrofuran (213 mL). Concentrate the reaction mixture under reduced pressure to an approximate volume of 250-270 mL, and heat to 60-65° C. for 2-3 hours. Cool the reaction mixture to 5-15° C. slowly and stir for 5-8 hours. Filter the resulting solids, wash the filter cake with ethyl acetate (56 mL). Transfer the solids to a clean reaction vessel, add ethyl acetate (150 mL), and heat to 60-65° C. for 2-3 hours, then cool the solution to 5-15° C. slowly. Stir for 2-3 hours at this temperature and collect the resulted solids by filtration. Wash the filter cake with ethyl acetate (45 mL) and dry the solids in an oven under reduced pressure below 60° C. to provide the title compound (21.0 g, 99.2% de, 100% ee, 51.0% yield) as an off white solid. MS (m/z): 341 (M+1).
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[CH3:10][O:11][N:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19](=[NH:22])[CH2:20][Cl:21])[CH2:15][CH2:14]1.Cl>O>[ClH:21].[CH3:10][O:11][N:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19](=[NH:22])[CH2:20][SH:5])[CH2:15][CH2:14]1
Reactant: CON=C1CCN(C(=N)CCl)CC1
Reactant: [O-]P([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON=C1CCN(C(=N)CS)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
1.03 g of trisodium phosphorothioate was added to a solution of 1.472 g of 2-(4-methoxyiminopiperidin-1-yl)-2-iminoethylchloride hydrochloride in 7 ml of water, kept cooled in ice-water, and the mixture was stirred at room temperature for about one hour. 5.7 ml of 1N hydrochloric acid were then added, followed by heating at 65° C. for 30 minutes. The resulting solution was concentrated under reduced pressure, mixed with ether, filtered to remove insolubles, and the filtrate concentrated under reduced pressure. The concentrate was mixed with isopropanol, and the crystals which separated out were collected by filtration and reprecipitated from a mixture of ethanol and ether, giving 850 mg of 2-(4-methoxyiminopiperidin-1-yl)-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1>O1CCCC1>[F:28][C:29]([F:37])([F:38])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH3:16])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:32][CH:31]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(α,α,α-trifluoro-p-tolyloxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.75 g of α,α,α-trifluoro-p-cresol in 75 ml of tetrahydrofuran at 80° C. for 24 hrs to give the product as a viscous oil.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:16]1([C:2]2[CH:15]=[CH:14][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Yield: 93.7 %

Procedure:
According to the general procedure described above, 4-Bromobenzophenone (131 mg, 0.50 mmol) reacted with phenylboronic acid (92 mg, 0.75 mmol) using 0.0005 mol % of Pd(dba)2, 0.002 mol % of Ph5FcP(t-Bu)2, and K3PO4 (318 mg, 1.50 mmol) in toluene solvent at 100° C. for 1 hr to title compound (121 mg, 94%) as a solid: 1H-NMR (400 MHz, CDCl3): δ 7.92 (d, 2H, J=8.4 Hz), 7.87 (d, 2H, J=7.2 Hz), 7.73 (d, 2H, J=8.4 Hz), 7.18 (d, 2H, J=6.8 Hz), 7.63 (m, 1H), 7.51 (m, 3H), 7.43 (m, 2H). 13C{1H}-NMR (100 MHz, CDCl3): δ 196.30, 145.16, 139.89, 137.68, 136.15, 132.34, 130.69, 129.96, 128.92, 128.26, 128.14, 127.25, 126.91. GC/MS(EI): m/z 181 (M−77+). Anal. Calcd for C19H14O: C, 88.34; H, 5.46. Found: C, 88.26; H, 5.62.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27](=O)[CH2:28][CH3:29].[Na]>ClC(Cl)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:27][CH2:28][CH3:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CC(NC1CCN(Cc3ccccc3)CC1)CC2
Reactant: CCC=O
Agent: [Na]
Solvent: CC(Cl)Cl
Product: CCCN(C1CCN(Cc2ccccc2)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine from Step 1 and propionaldehyde (4.5 mL, 62.4 mmol) in dichloroethane (200 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydrde (24 g, 0.113 mol, 2 eq.) in a single portion. The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica (10 g). This was placed on top of a flash column and eluted with 20% hexanes in acetone. The fractions containing product were pooled and concentrated to afford (1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine as a clear oil (6.86 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].[C:13]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:13][O:12][C:2]1[CH:1]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([OH:11])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2ccc(O)cc2c1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
To a mixture of naphthalene-2,7-diol (25 g, 156.08 mmol) and K2CO3 (32.3 g, 232.02 mmol) in acetone (300 ml) was added iodomethane (22.2 g, 156.41 mmol) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1%-10% ethyl acetate in petroleum ether to afford 7-methoxynaphthalen-2-ol as a light yellow solid (10 g, 37%). (ES, m/z): [M+H]+ 175.1; 1H NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 7.65 (d, J=8.8 Hz, 2H), 6.79 (dd, J=13.6, 1.6 Hz, 2H), 6.92-6.89 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:26][C:27]1(OCCCC)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCCOC1(OCCCC)CCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCC1
Yield: 29.2 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-di-n-butoxycyclopentane (2.14 g, 10 mmol) in the same manner as the example 20 to give the compound 35 (142 mg, 29.3%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:27])[NH:21]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:25]1[C:17]([F:16])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:27])=[CH:19]2)#[N:13]
Reactant: COc1cc2nccc(Cl)c2cc1C#N
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1C#N
Temperature: 95 °C
Yield: 35.1 %

Procedure:
A suspension of 4-chloro-6-cyano-7-methoxyquinoline (200 mg, 0.91 mmol), (prepared as described for the starting material in Example 1), 4-fluoro-5-hydroxy-2-methylindole (181 mg, 1.1 mmol), (prepared as described for the starting material in Example 11), and cesium carbonate (444 mg, 1.36 mmol) in DMF (6 ml) was heated at 95° C. for 2.5 hours. After cooling, the mixture was filtered, the filtrate was evaporated under vacuum and the residue was purified by column chromatography eluting with methylene chloride, followed by methanol/ethyl acetate/methylene chloride (2/10/88 followed by 5/15/80) to give 6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinoline (111 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14].N1C=CC=CC=1.[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14])(=[O:31])=[O:32]
Reactant: CC1=C(c2cc(F)ccc2N)C(=O)CC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: c1ccncc1
Product: CC1=C(c2cc(F)ccc2NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)CC1

Procedure:
0.700 g (3.14 mmol) of 2-(2-amino-5-fluorophenyl)-3-methyl-2-cyclopenten-1-one, 0.273 g (3.45 mmol) of pyridine, 0.754 g (3.45 mmol) of 2-mesitylenesulfonyl chloride, and 3 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (0.760 g, 60%).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:21])=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)(C(C)(C)C)(C)C.[F-].[K+]>CO>[F:21][C:10]1[C:11]([CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:18][CH:19]=[CH:20][C:9]=1[OH:8]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN2CCCC2)c1F
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: Oc1cccc(CN2CCCC2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of intermediate 33, 1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorobenzyl)pyrrolidine (19 g, 60 mmol) in MeOH (200 mL) was added KF (7.1 g, 120 mmol), and the mixture was stirred at RT for 1 h. The reaction mixture evaporated in vacuo. Water (100 mL) and concentrated HCl were added to attain pH˜6. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×100 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, the aqueous one was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo, recrystallized from Et2O/hexane mixture (1:1) to give the title compound (9.3 g, 78%, 48 mmol) as a yellow crystals. LCMS data: 197.1 and 196.1 (M+H)+ (calculated for C11H14FNO 195.24). 1H NMR data (DMSO-d6): 9.63 (s, 1H, OH), 6.87-6.96 (m, 1H, H—Ar), 6.71-6.85 (m, 2H, H—Ar), 3.58 (s, 2H, Ar—CH2); 2.36-2.46 (m, 4H), 1.61-1.72 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:37]1[CH2:40][O:39][CH2:38]1>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH:37]2[CH2:40][O:39][CH2:38]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)ccc34)cnc21
Reactant: IC1COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3nn(C4COC4)c4cc(F)ccc34)cnc21
Temperature: 100 °C
Yield: 86.4 %

Procedure:
In a microwave vial 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (300 mg, 0.73 mmol) was dissolved in DMF (5 ml) and cesium carbonate (714 mg, 2.19 mmol) and 3-iodooxetane (200 mg, 1.08 mmol) were added. The vial was sealed and heated at 100° C. under microwave irradiation for 2 h. The reaction was cooled, quenched with water and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 20% to 100% EtOAc/heptane to provide 295 mg (86%) of 2-(6-fluoro-1-oxetan-3-yl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 10.48 (s, 1H), 9.40 (s, 1H), 8.86 (dd, J=9.1, 5.3 Hz, 1H), 8.31 (s, 1H), 7.11-7.25 (m, 2H), 5.72-5.86 (m, 3H), 5.41 (t, J=6.6 Hz, 2H), 5.20 (t, J=7.4 Hz, 2H), 3.56-3.70 (m, 2H), 0.85-1.06 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19]CC4C=CC(OC)=CC=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nccc(-c3c[nH]nc3-c3ccc(F)cc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1

Procedure:
A solution of 4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine prepared in accordance with Example A-305 (0.35 g, 0.00093 mol) in 15 mL of trifluoroacetic acid was heated at reflux for 16 hours. Solvent was removed and the residue was partitioned between ethyl acetate and 1 N ammonia hydroxide. Organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate) to give 0.14 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine, as a pale yellow solid (59% yield), mp: 273-274° C.; Anal. Calc'd for C13H10FN5.0.25H2O: C, 60.11; H, 4.07; N, 26.96. Found: C, 60.15; H, 3.82; N, 26.38.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=3[CH:22]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH:23]([N:26]1[CH2:31][CH2:30][N:29]([C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]4)=[CH:22][C:15]=3[CH:16]=2)=[O:21])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCC(Oc2ccc3oc(C(=O)O)cc3c2)CC1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2ccc3oc(C(=O)N4CCN(C(C)C)CC4)cc3c2)CC1
Yield: 55.9 %

Procedure:
In a flask were mixed together the above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzofuran-2-carboxylic acid (0.220 g, 0.549 mmol, corrected for purity), 1-isopropylpiperazine (0.084 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (0.291 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropyl-amine (0.225 mL) in 2.2 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=4/96) produced 0.127 g of the title compound as light yellow oil.