Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[CH:35][N:36]=2)[N:33]=1.C(=O)(O)[O-].[Na+]>>[C:1]1([CH:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([N:34]=[CH:35][N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Clc1ccc2ncnn2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(C(OC2CCN(CCCCCNc3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Yield: 66.9 %

Procedure:
0.705 g of 4-(diphenylmethoxy)-1-piperidinepentanamine and 0.309 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine were stirred at 135-140° C. for 1.5 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (95:5:1). The desired fraction was collected, recrystallized from ethyl ether and dried to yield 0.629 g of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:9][CH3:10])[CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[Li]CCCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>C1COCC1>[CH3:1][C@@H:2]([CH2:9][CH3:10])[CH2:3][C:4]1[O:5][C:6]([Sn:17]([CH3:19])([CH3:18])[CH3:16])=[CH:7][CH:8]=1
Reactant: C[Sn](C)(C)Cl
Reactant: CC[C@H](C)Cc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C)Cc1ccc([Sn](C)(C)C)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of (S)-2-(2-methylbutyl)furan (4.10 g, 29.7 mmol) in dry THF (100 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 18.0 mL, 45.0 mmol) was then added slowly. This mixture was stirred at −78° C. for additional 20 minutes, and then allowed to warm to room temperature and stirred at room temperature for 60 minutes, before it was cooled back to −78° C. A solution of trimethylstannyl chloride (1.0 M, 45 mL, 45.0 mmol) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water (20 mL), and reaction mixture was diluted with hexane (300 mL), washed with water (200 mL×2), dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (7.43 g, 83.2%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Brc1cccc2cn[nH]c12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(-c2cccc3cn[nH]c23)c(Cl)c1
Temperature: 80 °C
Reaction time: 19 h

Procedure:
A solution of 7-bromo-1H-indazole (3; 1.01 g, 5.13 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.176 g, 0.152 mmol) in 15 mL of ethylene glycol dimethyl ether was stirred for 30 m. To the solution was added 2,4-dichlorophenyl boronic acid (1.93 g, 10.1 mmol) and a 2 M aqueous Na2CO3 solution (7.1 mL, 14.2 mmol). The orange-yellow mixture was stirred at 80° C. for 19 h, allowed to cool, then partitioned between 50 mL of ethyl acetate and 50 mL of water. The organic layer was dried over MgSO4, filtered, and concentrated to an orange oil. Column chromatography (0→10% EtOAc/hexanes) afforded of 7-(2,4-dichloro-phenyl)-1H-indazole as a pale yellow foamy solid (4; 1.12 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=2)=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 3,4-difluoro-phenyl isocyanate (0.075 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 55 as a colorless solid (0.062 g, 35%). LCMS m/z (%)=423 M+H+ (37Cl, 23), 421 M+H+ (35Cl, 27), 1H NMR (400 MHz, acetone-d6) δ: 8.199 (d, J=2.44 Hz, 1H), 8.181 (d, J=2.42 Hz, 1H), 8.166 (d, J=2.37 Hz, 1H), 8.147 (d, J=2.08 Hz, 1H), 8.106 (d, J=2.65 Hz, 1H), 8.085 (d, J=2.68 Hz, 1H), 7.967 (s, 1H), 7.880 (d, J=2.61 Hz, 1H), 7.627 (t, 1H), 7.594 (d, J=3.86 Hz, 1H) 7.563 (d, J=8.96 Hz, 1H), 4.669 (m, 1H), 4.242 (s, 3H), 1.874 (d, J=6.61 Hz, 3H), 1.713 (d, J=6.61 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][C:27]3([F:33])[F:32])=[CH:22][CH:21]=2)=[N:10]1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:41](=[O:43])[CH3:42])[CH2:28][C:27]3([F:32])[F:33])=[CH:24][CH:25]=2)=[N:10]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1nccc2c1c(-c1ccc(C3CCNCC3(F)F)cc1)nn2-c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nccc2c1c(-c1ccc(C3CCN(C(C)=O)CC3(F)F)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a mixture of 1-(2,6-difluorophenyl)-3-(4-(3,3-difluoropiperidin-4-yl)phenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridine (186 mg) and triethylamine (91.0 mg) in dichloromethane (4 mL) was added acetic anhydride (67.0 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and diluted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (200 mg).
Reaction SMILES: C(ON=O)CC(C)C.[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:23])[C:16]([CH3:22])=[C:17]([C:20]#[N:21])[C:18]=1N)=[O:13])[CH3:10].[I:24]CI.O>C(#N)C>[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:23])[C:16]([CH3:22])=[C:17]([C:20]#[N:21])[C:18]=1[I:24])=[O:13])[CH3:10]
Reactant: ICI
Reactant: CCOC(=O)c1c(N)c(C#N)c(C)n1C
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(I)c(C#N)c(C)n1C
Temperature: 55 °C

Procedure:
Add isoamylnitrite (2.5 Eq.) to 3-amino-4-cyano-1,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in preparation 44) and diiodomethane (3.5 eq.) in acetonitrile (10 mL) with stirring at 55° C. under a nitrogen atmosphere. Slowly heat the reaction mixture to 75° C. and heat at this temperature for 3 hours. Cool to room temperature and pour into water, and extract the quenched reaction with ethyl acetate. Wash the organic extracts with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum. Purify the residue by silica gel chromatography (Prep.2000) eluting with methylene chloride to provide a solid. Recrystallize from ethyl acetate to provide the title compound as crystals. Mass spectrum (m/e): 318.0 M*). (Bruker 300) 1H NMR (CDCl3) 4.31-4.38 (2H, dd), 3.83-3.86 (3H, s), 2.41-2.44 (3H, s), 1.40-1.44 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1>>[CH2:57]([N:54]1[CH2:53][CH2:52][N:51]([S:48]([C:45]2[CH:46]=[CH:47][C:42]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:43][CH:44]=2)(=[O:49])=[O:50])[CH2:56][CH2:55]1)[CH3:58]
Reactant: CCN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(S(=O)(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)cc2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 1-(4-bromo-benzenesulfonyl)-4-ethyl-piperazine (prepared from 4-bromo-benzenesulfonyl chloride and N-ethylpiperazine in acetonitrile, 68 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of (5-{7-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-bis-(4-methoxy-benzyl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-96) as an ivory powder (70 mg, 69%).
Reaction SMILES: CC(C1C=CC(C2CNCCC=2)=C(O)C=1)(C)CCCCCC.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH3:33][C:34]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH2:49][N:50]([CH2:54][CH:55]=[CH2:56])[CH2:51][CH2:52][CH:53]=2)=[C:44]([O:57]CC=C)[CH:43]=1)([CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(O)C>[CH3:41][C:34]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH2:49][N:50]([CH2:54][CH:55]=[CH2:56])[CH2:51][CH2:52][CH:53]=2)=[C:44]([OH:57])[CH:43]=1)([CH3:33])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: C=CCOc1cc(C(C)(C)CCCCCC)ccc1C1=CCCN(CC=C)C1
Agent: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C=CCBr
Product: C=CCN1CCC=C(c2ccc(C(C)(C)CCCCCC)cc2O)C1
Yield: 22 %

Procedure:
A mixture of 1.0 g. (3.32 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine, 539 mg. (3.90 mmoles) of anhydrous potassium carbonate and 401 mg. (3.32 mmoles) of allyl bromide in 23 ml. of ethanol is heated at reflux for 23 hours. The reaction mixture is concentrated under reduced pressure and the residue dissolved in 250 ml. of saturated sodium bicarbonate and 200 ml. of dichloromethane. The organic extract is washed once with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil is purified via column chromatography on 125 g. of silica gel eluted with 5% methanol-dichloromethane to yield 372 mg. (29%) of 3-[4-(1,1-dimethylheptyl)-2-allyloxyphenyl]-1-N-(2-propenyl)-1,2,5,6-tetrahydropyridine as an oil and 247 mg. (22%) of the title compound, M.P. 109°-110° C. (from ether-pentane).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].Cl[CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>C1COCC1>[CH3:1][O:2][N:3]([CH2:14][CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(CCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
To a cooled (0° C.) solution of tert-butyl methoxycarbamate (2.35 g, 16.0 mmol) in THF (50 mL) was slowly added NaH (0.640 g, 16.0 mmol). After stirring at 0° C. for 5 minutes and then at room temperature for 30 minutes, the mixture was added dropwise to a solution of 3-chloro-1-phenylpropan-1-one (2.84 g, 16.8 mmol) in THF (25 mL). After stirring at room temperature for 30 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed (10% ethyl acetate in hexanes) to provide the product (1.80 g, 40% yield) as a clear oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C@H:5]12[CH2:13][C@H:9]([O:10][C:11]1=[O:12])[CH:8]=[CH:7][CH2:6]2>O.C1COCC1>[N:1]([C@H:9]1[CH:8]=[CH:7][CH2:6][C@H:5]([C:11]([OH:12])=[O:10])[CH2:13]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1O[C@@H]2C=CC[C@H]1C2
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H]1C=CC[C@H](C(=O)O)C1

Procedure:
A solution of 10.6 g of sodium azide in 70 ml of water is added to a solution of 18.4 g of racemic cis-6-oxabicyclo[3.2.1]oct-3-en-7-one in 175 ml of THF. The reaction mixture is then heated to reflux for 15 hours. The THF is subsequently stripped off in a rotary evaporator at a bath temperature of 30° C. The remaining aqueous phase is mixed with 165 ml of 2 molar sodium hydroxide solution and extracted twice with 110 ml of toluene each time and once with diethyl ether. The aqueous phase is then acidified with concentrated hydrochloric acid at about 10° C. The product is extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulphate, filtered and concentrated. 19.7 g of an oil, which becomes solid under storage in a refrigerator, are obtained. Assignment of the product to the trans isomer results from the experience that reactions of this type take place with inversion of the stereochemistry at the reaction site.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:22])[CH3:2].Br>C(O)(=O)CC>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:22])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(Nc3ccc(OC)cc3)nc21
Agent: Br
Solvent: CCC(=O)O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(O)cc3)nc21
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 8-ethyl-2-(4-methoxyphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (133 mg, 0.45 mmol) and 1 mL of 48% aqueous HBr in 10 mL of propionic acid was heated at reflux for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined and washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant solid was purified by dissolving in ethyl acetate and passing the solution through silica gel to provide 58 mg (46%) of 8-ethyl-2-(4 hydroxyphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 222-224° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=4[O:32][CH3:33])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 84.7 %

Procedure:
A stirred of mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (1.9 g, 0.0086 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone 2.6 g, 0.0086 mol), K2CO3 (1.2 g), and acetonitrile (7.5 ml) was refluxed for 6 hr. The reaction was poured into water and a white solid settled from solution. This was collected, dried and afforded 3.2 g of product. The product was recrystallized from ethanol to yield 2.7 g (71%) of 1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxy-3-methoxyphenyl]ethanone as glistening white flakes, m.p.=158°-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:9][C:10]=2[CH3:26])=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Yield: 44 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethyl ester, 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (American Home Products U.S. Pat. No 3,795,691) (7.06 g, 31.5 mmol) and Cs2CO3 (13.3 g, 41.0 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (250 mL) and H2O (250 mL), and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, hexanes to 10% ethyl acetate/hexanes) to provide 2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (6.81 g, 44%) as a off-white solid. Rf=0.39 in 1:4 ethyl acetate: hexanes; 1H NMR (400 MHz, CDCl3) δ8.11 (t, J=1.6 Hz, 1H), 7.89-7.86 (m, 1H), 7.49 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 6.80-6.72 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.15 (t, J=6.6 Hz, 2H), 2.92 (t, J=6.6 Hz, 2H), 2.34 (s, 3H), 1.49 (s, 6H), 1.24 (t, J=7.2 Hz, 3H); MS (EI) 510.1 (M+Na)+, 488.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].C(O)C.[NH2:6][C:7]1[N:11]([C:12]2[CH:21]=[CH:20][C:15]3[NH:16][C:17]([CH3:19])=[N:18][C:14]=3[CH:13]=2)[N:10]=[CH:9][C:8]=1[C:22]([C:24]1[N:25](S(C2C=CC=CC=2)(=O)=O)[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23]>O>[NH2:6][C:7]1[N:11]([C:12]2[CH:21]=[CH:20][C:15]3[NH:16][C:17]([CH3:19])=[N:18][C:14]=3[CH:13]=2)[N:10]=[CH:9][C:8]=1[C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23]
Reactant: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccccc5n4S(=O)(=O)c4ccccc4)c3N)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccccc5[nH]4)c3N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
An aqueous solution (1.67 ml) of 4 M sodium hydroxide was added to an ethanol solution (17 ml) of [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1-benzenesulfonyl-1H-indol-2-yl) methanone (87 mg). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water. The resulting solid was collected by filtration, washed with water, and dried to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl) methanone (40 mg, 63%).
Reaction SMILES: [Si:1]([O:18][C@H:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]1[CH2:31][OH:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35](OC)=[O:36].O1CCCC1.[H-].[Na+]>O>[Si:1]([O:18][C@H:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]1[CH2:31][O:32][CH2:34][CH2:35][OH:36])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1CO
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1COCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 48 (4.56 g), methyl bromoacetate (2.22 mL) and tetrahydrofuran (25 mL) were stirred at 0° C., 60% sodium hydride suspension (400 mg) was added into the solution. The reaction solution was stirred at room temperature for overnight, added water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→85:15). The obtained compound (1.46 g) was added tetrahydrofuran (20 mL), methanol (1 mL) and lithium borohydride (117 mg) and stirred at room temperature for 2 hours. The reaction solution was added water and aqueous 5% potassium sulfate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (1.40 g) having the following physical properties.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[O:6][N:5]=1)([CH3:3])[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CC(C)c1noc(N2CCCCC2=O)n1
Product: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared from 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-2-one and cyclopropylamine following a procedure analogous to that described for Intermediate 66.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23](Br)[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.Cl>C([O-])(=O)C.[K+].C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([C:31]4[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=4)[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Cn1cc(-c2cnc3c(c2)c2c(O)c(C#N)ncc2n3S(=O)(=O)c2ccccc2)cn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (500 mg, 1.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.40 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (200 mg, 0.25 mmol) in 2N aqueous potassium acetate (3.6 mL) and acetonitrile (7.2 mL) was heated under microwave irradiation at 140° C., for 30 minutes. The reaction mixture was allowed to cool to ambient temperature, 1M hydrochloric acid (7.5 mL) was added and the mixture was stirred at room temperature for 1 h. The resulting precipitate was collected by filtration, washed with acetonitrile (5 mL) and left to air dry to afford the title compound as a crude brown solid (500 mg, 99%). LCMS (Method G): RT=3.84 min, M+H+=431.