Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1cccc(CNC(=O)c2c(N)ncnc2Cl)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CNC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Yield: 59.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (92 mg, 0.34 mmol), 4-amino-6-chloro-N-(3-methoxybenzyl)pyrimidine-5-carboxamide (100 mg, 0.34 mmol), DIEA (360 μl, 2.07 mmol) and cesium fluoride (157 mg, 1.03 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated to reflux for 48 h. The solvent was evaporated under reduced pressure and the crude was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (0% to 40%, dichloromethane-ethyl acetate) to obtain 106 mg (59% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16](=O)[NH2:17])=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>O1CCCC1>[Br:1][C:2]1[C:3]([C:16](=[S:28])[NH2:17])=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(N)=O)c(Br)cn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C(N)=S)c(Br)cn1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
The crude tert-butyl 5-bromo-4-carbamoylpyridin-2-ylcarbamate (Intermediate 84, 232 mmol) was treated with Lawesson's Reagent (94 g, 232 mmol, 1 eq) and tetrahydrofuran (700 mL), the resulting mixture was heated at reflux for 1 h, then it was allowed to stir at room temperature over the weekend. The mixture was concentrated to dryness in vacuo and toluene (˜300 mL) was added. A bright yellow solid precipitated formed which was collected by filtration and washed with toluene, then dried in the vacuum oven at 50° C. for 4 h, yielding 75 g of a bright yellow solid (97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([OH:17])=O)[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([N:31]1[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]1)=[O:17])[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1
Reactant: OC1CCNCC1
Reactant: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CC(=O)O)c2cc1OC
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CC(=O)N3CCC(O)CC3)c2cc1OC
Yield: 38.8 %

Procedure:
2-[5,6-Dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone is prepared by following the procedure described in example 93, but using 0.2 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]acetic acid and 0.07 g of 4-hydroxypiperidine. After purification by flash-pack chromatography (silica, 98/02 by volume dichloromethane/methanol as eluents), 0.096 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone is obtained, the characteristics of which are as follows:
Reaction SMILES: C([N:4](C(=O)C)[C:5]1[N:9]([C:10](=[N:24]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:8]=[C:7]([CH3:36])[C:6]=1[Cl:37])(=O)C.[OH-:41].[Na+]>CO>[C:14]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]([NH:13][CH2:12][CH2:11][CH:10]1[N:24]=[N:4][C:5]2=[C:6]([Cl:37])[C:7]([CH3:36])=[N:8][N:9]12)=[O:18])([OH:41])=[O:23]
Reactant: [OH-]
Reactant: CC(=O)N(C(C)=O)c1c(Cl)c(C)nn1C(CCN1C(=O)c2ccccc2C1=O)=NOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CO
Product: Cc1nn2c(c1Cl)N=NC2CCNC(=O)c1ccccc1C(=O)O
Yield: 49 %

Procedure:
380 mg (0.65 mmol) of 5-bisacetylamino-4-chloro-3-methyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)pyrazole, mixed with 15 ml methanol and 15 ml of 2N sodium hydroxide solution, are heated under reflux for 10 minutes. The solution is then filtered, neutralised and freed of methanol under vacuum. The crystals which precipitate from the aqueous solution are separated off and washed with water. They may be recrystallised from a 1:1 water/ethanol mixture. 110 mg (49%) of 3-[2-[2-carboxy-benzamido)ethyl]-7-chloro-6-methyl-pyrazolo[5,1-c][1,2,4]triazole with a m. pt. of 162°-166° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.[Li]CCCC.CCCCCC.[CH3:25][O:26][CH2:27]Br>C1COCC1>[CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[C@H:7]([CH2:25][O:26][CH3:27])[N:8]=1
Reactant: COCBr
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC
Reaction time: 8 h

Procedure:
To a solution of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine (5.53 g, 30 mmol) in anhydrous THF (80 ml) a 1.6M solution of n-BuLi in hexane (10.85 ml, 17.36 mmol) was added at -78° C. After 30 minutes a solution of bromomethyl methyl ether (4.5 g, 36 mmol) in THF (20 ml) was added dropwise. The reaction mixture was allowed to come to 20° C. overnight and was quenched by addition of 1M phosphate buffer (pH 7, 80 ml). The turbid mixture was stirred for 10 minutes, diluted with water (250 ml) and diethyl ether (180 ml). The layers were separated and the aqueous phase extracted with diethyl ether (2×150 ml). The combined organic layer was dried (Na2SO4), concentrated and purified by flash chromatography (silica gel; hexane:diethyl ether 5:1) to yield 5.61 g. To remove final impurities of the other diastereomer the material was crystallized from acetonitrile at -30° C. and the cold precipitate redissolved in CH2Cl2, dried (Na2SO4) and concentrated.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]1/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1.Cl>C1COCC1>[Cl:28][C:24]1[CH:23]=[C:22]([CH2:21][CH:20]([OH:29])/[CH:19]=[CH:18]/[C@H:13]2[CH2:14][CH2:15][C:16](=[O:17])[N:12]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]([OH:30])=[O:4])[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Aqueous lithium hydroxide (1.0 N, 0.04 mL) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester (16 mg, 0.039 mmol) in THF (0.25 mL) at rt. After 1 h, aqueous HCl (0.5 N, 3 mL) was added and the mixture was extracted with ETOAc (2×5 mL). The combined organic phase was washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 15 mg (97%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[C:13]=3[CH2:23][OH:24])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[F:22][C:14]1[C:13]([CH2:23][OH:24])=[C:12]2[C:17]([N:18]3[C@H:10]([CH2:11]2)[CH2:9][NH:8][CH2:20][C@H:19]3[CH3:21])=[N:16][CH:15]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3c(ncc(F)c3CO)N21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNC[C@H]2Cc3c(ncc(F)c3CO)N21
Reaction time: 18 h
Yield: 76.4 %

Procedure:
A mixture of 0.040 g (4R,9aR)-7-fluoro-8-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 1 mL of a 2M solution of hydrochloric acid in dioxane was kept at room temperature for 18 h. The solvents were evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia (25% in water ) (9:1:0.1). The product fractions were collected and evaporated to yield 0.0215 g of yellowish foam.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([N:14]2[C:18](Cl)=[N:17][N:16]=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:20]1[O:22][CH:21]1[CH2:23][OH:24]>CCCCCC>[O:22]1[CH2:20][CH:21]1[CH2:23][O:24][C:18]1[N:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]=[N:16][N:17]=1
Reactant: OCC1CO1
Reactant: Clc1nnnn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: c1ccc(-n2nnnc2OCC2CO2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium hydride (11.9 g., 0.050 mole), washed free of mineral oil with hexane, was stirred in 1.8 l. of DMF at ice-water temperature while a solution of 72.3 g (0.40 mole) of 1-phenyl-5-chlorotetrazole and 29.6 g. (0.04 mole) of glycidol in 1.8 l. of DMF was added dropwise during 4 hours. The solution was allowed to stand at 25° overnight (16 hours), diluted with 12 l. of H2O and extracted with ethyl acetate. The extracts were washed with water, dried (Na2SO4), and evaporated to give 75.7 g. of product, m.p. 77°-81°. Recrystallization from MeOH-i-PrOH gave 55.8 g., m.p. 83°-84°.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH:35]([CH2:38][CH2:39][CH3:40])[CH2:36][OH:37]>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH:35]([CH2:36][OH:37])[CH2:38][CH2:39][CH3:40])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: CCCC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1-pentanol using conditions similar to those employed in Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.31 (1H, d, J=8 Hz), 8.55 (1H, s), 8.12 (1H, s), 7.40 (2H, dd, J=6, 9 Hz), 7.13 (2H, t, J=9 Hz), 4.93 (1H, t, J=5 Hz), 4.30-4.46 (2H, m), 4.15 (2H, s), 3.94-4.03 (1H, m), 3.32-3.53 (6H, m), 1.88-2.05 (2H, m), 1.68-1.82 (2H, m), 1.42-1.64 (2H, m), 1.25-1.36 (2H, m), 0.88 (3H, t, J=7 Hz); ES+ MS: 511 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([F:18])=[C:11]([Cl:10])[CH:12]=2)=[O:9])[O:4][N:3]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cc(Br)no1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cc(Br)no1

Procedure:
This material was prepared according to the procedure of Example 1, Step C, using 3-bromoisoxazole-5-carboxylic acid and 3-chloro-4-fluoro aniline as starting materials. MF=C10H5BrClFN2O2; LCMS calculated for C10H5BrClFN2O2 (M+H)+: m/z=319.
Reaction SMILES: C([N:5]1[C:9](=O)[N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[S:6]1)CCC.C([C:16]([O:18][CH3:19])=[O:17])#N>ClCCl>[CH3:19][O:18][C:16]([C:9]1[N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[S:6][N:5]=1)=[O:17]
Reactant: COC(=O)C#N
Reactant: CCCCn1sc2nccn2c1=O
Solvent: ClCCl
Product: COC(=O)c1nsc2nccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a cooled solution of 2-butylimidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-one (2.95 g, 15.0 mmole) in 25 mL dichloromethane, methyl cyanoformate (2.54 g, 30 mmole) was added dropwise and the mixture was stirred for 16 h at room temperature. The precipitate was filtered and subsequently washed with dichloromethane to give 2.18 g (80%) of 3-(methoxycarbonyl)imidazo[1,2-d]-1,2,4-thiadiazole as colourless crystals: mp 164.5°-165° C.; 1H NMR (CDCl3) δ8.13 (s, 1H), 7.51 (s, 1H), 4.11 (s, 3H) ppm; IR (KBr) δ3440, 1737, 1527, 1253, 1071 cm-1. Anal. Calcd for C6H5N3 O2S: C, 39.34; H, 2.75; N, 22.94. Found: C, 39.41; H, 2.51; N, 22.94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][N:11]=[N+]=[N-])=[CH:4][CH:3]=1.CP(C)C.O.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:10][NH2:11])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCC(Oc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CP(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: NCC(Oc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 203.2 %

Procedure:
To a solution of 2-(4-chlorophenoylxy)-2-(4-chlorophenyl)ethyl azide (Step B, 0.23 g, 0.75 mmol) in 4 mLTHF at −20° C. was added trimethylphosphine (0.18 mL, 1.8 mmol), and the reaction was allowed to warm to room temperature over 2 h. Lithium hydroxide monohydrate (61 mg, 1.5 mmol) was added followed by 2 mL water. After stirring at room temperature for 30 min, the reaction was quenched by addition of 2 M hydrochloric acid (final pH=2). The volatile materials were removed on a rotary evaporator, and the resulting mixture was partitioned between brine (20 mL), 5 N aqueous sodium hydroxide (20 mL), ether (20 mL) and toluene (20 mL). The organic layer was separated and the aqueous layer extracted with ether (40 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound (0.43 g), which was contaminated with trimethylphosphine oxide and was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.46-7.40 (m, 4H), 7.20 (d, 2H), 6.91 (d, 2H), 5.53 (m, 2H), 3.36 (m, 2H). LC-MS: m/e 282 (M+H)+ (2.5 min).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]([NH2:34])[CH3:33])=[CH:27][CH:26]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:34][CH:32]([CH3:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: CC(N)Cc1ccc(Cl)cc1
Product: CC(Cc1ccc(Cl)cc1)NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid was coupled with (±)-2-(4-chlorophenyl)-1-methylethylamine as in EXAMPLE 1, Part C. HPLC: RT=10.50 min. MS (ESI−): mass calcd. for C22H18BrClN4O3S2, 563.97; m/z found, 563/565 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.61 (s, 1H), 8.37 (dd, J=7.0, 1.2, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.88 (d, J=1.8, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.32-7.25 (m, 2H), 7.13-7.05 (m, 2H), 7.07 (dd, J=8.4, 1.8, 1H), 7.01 (d, J=8.4, 1H), 5.74 (br d, J=7.8, 1H), 4.40-4.28 (m, 1H), 2.88 (dd, J=13.6, 5.6, 1H), 2.75 (dd, J=13.6, 7.1, 1H), 1.17 (d, J=6.7, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(NCCN2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCN3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a solution of 2-fluoro-N1-(2-morpholinoethyl)benzene-1,4-diamine (0.50 g, 2.09 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (3.2 mL, 6.40 mmol, 2 M in toluene) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (0.65 g, 4.13 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 36 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH (V/V)=30:1) to give the title compound as a white solid (0.50 g, 24%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10](COCC[Si](C)(C)C)[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=3)[N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)c1ccc(Cn2nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 3 %

Procedure:
To a solution of 4-{[3-[[(5-chloro-2-thienyl)sulfonyl]({[2-(trimethylsilyl)ethyl]oxy}methyl)amino]-4-(methyloxy)-1H-indazol-1-yl]methyl}-N,N-diethylbenzamide (for a preparation see Intermediate 79) (125.5 mg, 0.189 mmol) in dichloromethane (DCM) (1 ml) was added dropwise TFA (0.292 ml, 3.78 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 30 h. Reaction mixture was concentrated under a stream of nitrogen in a blowdown unit. The residue was purified using the high pH-MDAP and further purified by MDAP to give the title compound (3 mg, 3%) LCMS (System A) RT=1.19 min, ES+ve m/z 533/535 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([C:30]4[CH:31]=[CH:32][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][CH:29]=4)[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: O=C(c1cccc(I)c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1ccc(-c2cccc(C(=O)c3cn(C4CCCC4)c4ncnc(Cl)c34)c2)cc1
Yield: 47 %

Procedure:
A solution of (4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-iodo-phenyl)-methanone (100 mg, 0.22 mmol), 4-(dimethylamino)Phenyl boronic acid (42.9 mg, 0.26 mmol), PdCl2(PPh3)2 (7.7 mg, 0.011 mmol), and K2CO3 (45.6 mg, 0.33 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was heated to 90° C. After 24 h the reaction was diluted with EtOAc and filtered through celite. The filtrate was washed with water, dried over Na2SO4, and concentrated. Purification by flash column chromatography (hexanes/ethyl acetate 8:2) afforded the title compound as a white solid (46 mg, 47%). MS: 445.1/447.1 (MH+); HPLC Rf: 8.05 min. (HPLC method 4).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N)CCCCCCCCCCC.C=CCCCCCCCCCC>>[CH2:4]([N:2]([CH3:3])[CH3:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCO
Reactant: CNC
Agent: C=CCCCCCCCCCC
Agent: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCN(C)C
Reaction time: 0.01 h

Procedure:
50 grams of the said catalyst is charged into a reactor tube, for example as shown and described in O.S. II page 389, and the tube is heated preferably to 360° C. and it is well to condition the tube with a flow of air (as about 500 ml. per minute) for a period of hours. The air flow then is discontinued, and approximately two milli-equivalents of dimethyl amine and 1 milli-equivalent of dodecyl alcohol, per minute, are simultaneously charged into the reactor tube. The outflow is essentially 95% dodecyl amine and 5% dodecene, as determined by G.L.C. If any dodecyl alcohol is present in the product, this indicates that the through-put was too fast, and the residence time of the reacting materials in the tube or column may be set at about 30 seconds.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[N:9]([CH2:15][C:16]3[CH:37]=[CH:36][C:19]4/[C:20](=[CH:29]/[C:30]5[NH:34][C:33](=[O:35])[O:32][N:31]=5)/[C:21]5[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=5[CH2:23][CH2:24][C:18]=4[CH:17]=3)[C:10]([CH2:12][CH2:13][CH3:14])=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=[CH:3]1>C1COCC1.[Pt](=O)=O>[O:1]=[C:2]1[C:8]2[N:9]([CH2:15][C:16]3[CH:37]=[CH:36][C:19]4/[C:20](=[CH:29]/[C:30]5[NH:34][C:33](=[O:35])[O:32][N:31]=5)/[C:21]5[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=5[CH2:23][CH2:24][C:18]=4[CH:17]=3)[C:10]([CH2:12][CH2:13][CH3:14])=[N:11][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCCc1nc2ccccc(=O)c2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1noc(=O)[nH]1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CCCc1nc2c(n1Cc1ccc3c(c1)CCc1ccccc1/C3=C\c1noc(=O)[nH]1)C(=O)CCCC2
Temperature: 25 °C
Reaction time: 7 h
Yield: 24.3 %

Procedure:
Compound 39 (50 mg, 0.1 mmol) obtained in Example 39 was dissolved in THF (1 mL), and platinum (IV) oxide (23 mg, 0.1 mmol) was added under nitrogen atmosphere. Under hydrogen atmosphere, the mixture was stirred at room temperature for 7 hr. The mixture was filtrated, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (hexane/ethyl acetate=1/4) to give the title compound (compound 41, 12 mg, 24%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:11]2[CH:10]=[CH:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: COc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-n2ccnc2-c2ccccc2)cc1
Yield: 25 %

Procedure:
A mixture of 28.8 parts of 2-phenyl-1H-imidazole, 37.4 parts of 1-bromo-4-methoxybenzene, 20 parts of potassium carbonate and 180 parts of N,N-dimethylacetamide is stirred for one week at reflux temperature. The reaction mixture is cooled, poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are dried, filtered and evaporated, yielding 10 parts (25%) of 1-(4-methoxyphenyl)-2-phenyl-1H-imidazole as a residue.