Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:5]=1
Reactant: O=[N+]([O-])c1ccn(CCc2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccn(CCc2ccccc2)n1
Reaction time: 8 h

Procedure:
To a solution of 3-nitro-1-phenethyl-1H-pyrazole (90 mg, 0.41 mmol) in ethyl acetate (2 mL) and ethanol (2 mL) was added 10% Pd—C (20 mg), the resulting mixture was stirred under hydrogen atmosphere overnight. TLC showed the reaction was complete. The catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated under reduced pressure to give the title compound as colorless oil. LC-MS (ES, Pos.): 188 [MH+]. 1H NMR (CDCl3, 400 MHz): δ=3.10 (t, J=7.2 Hz, 2H), 3.64 (br s, 2H), 4.12 (t, J=7.2 Hz, 2H), 5.51 (d, J=2.3 Hz, 1H), 6.91 (d, J=2.3 Hz, 1H), 7.08-7.11 (m, 2H), 7.20-7.30 (m, 3H).
Reaction SMILES: [CH2:1]([C:4]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[NH:12]2)[CH:2]=[CH2:3].Cl.Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C:4]1[C:16]([O:17][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[NH:12]2)[CH:2]=[CH2:3]
Reactant: ClCc1ccc2ccccc2n1
Reactant: C=CCc1c(O)ccc2[nH]c3c(c12)CCCC3CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccc3ccccc3n2)ccc2[nH]c3c(c12)CCCC3CC(=O)OCC
Reaction time: 48 h

Procedure:
The compound from Step 4 (400 mg) is dissolved in 3.0 ml of DMF and 400 mg of 2-(chloromethyl)quinoline hydrochloride is added, followed by 275 mg of K2CO3. The reaction is stirred for 48 hours, 3.0 ml of H2O is added and the product extracted into Et2O. After washing with brine, the organic phase is dried and evaporated to yield ethyl 5-allyl-6-(quinolin-2-ylmethoxy)-1,2,3,4-tetrahydrocarbazol-1-ylacetate.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O>C1COCC1>[CH2:33]([O:32][C:30](=[O:31])[C:11]1[C:12]([F:15])=[CH:13][CH:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]=1[F:16])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of dibenzyl-(2,4-difluoro-phenyl)-amine (17.5 g, 0.056 mol) in THF (140 mL), under nitrogen atmosphere, cooled at −78° C., n-butyllithium (1.6 M in hexane, 38 mL, 0.06 mol) was slowly added. The reaction was stirred for 1 hour, and then quickly added via a cannula to a solution of benzyl chloroformate (11.78 mL, 0.084 mol) in THF (140 mL) previously cooled at −78° C. The reaction was then allowed to warm to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane grading to 10% acetate (quant.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:2]=2[O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1OC
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2cncc(C#N)c2Oc2ccc3[nH]ccc3c2)cc1OC
Temperature: 80 °C
Yield: 74 %

Procedure:
A mixture of 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (120 mg, 0.44 mmol), 5-hydroxyindole (71 mg, 0.53 mmol) and K2CO3 (91 mg, 0.66 mmol) in CH3CN (4.0 mL) was heated at 80° C. for 4 h. After cooling to r.t., the reaction mixture was diluted with water (20 mL) and the precipitate was collected by filtration and washed with ether containing MeOH to give 121 mg (74%) of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-yloxy)nicotinonitrile 220 as a tan solid. MS: 372.2; melting range: 192-194° C.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2].[NH2:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].N1C=CC=CC=1>ClCCl>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:10][C:1]([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2])[CH:19]=1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)OCC(Cl)(Cl)Cl)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Troc-Cl (0.76 ml, 5.56 mmol) in dry dichloromethane (10 mL) was added dropwise to 2-amino-4,5-dimethoxybenzoic acid 102 (1 g, 5.1 mmol) and pyridine (0.82 ml, 10.1 mmol) in dry dichloromethane (20 ml) at 0° C. The reaction mixture was allowed to stir overnight at room temperature and then washed with dilute HCl (1N, 2×25 ml), water (2×25 ml) and brine (20 ml). The organic phase was dried over MgSO4 and evaporated to yield of crude product (1.6 g), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(c1csc(Br)c1)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: O=C(c1csc(-c2ccccc2Cl)c1)N1CCCCC1
Temperature: 140 °C
Yield: 58.1 %

Procedure:
(5-Bromo-thiophen-3-yl)-piperidin-1-yl-methanone (75 mg, 0.27 mmol) was dissolved in dimethoxyethane (1 mL) and ethanol (1 mL). 2-Chlorophenylboronic acid (0.54 mmol), [1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II) (0.014 mmol) and caesium carbonate (0.41 mmol) were added and the reaction mixture heated to 140° C. using microwave irradiation for 1 hour. The solvent was removed under vacuum and the residue dissolved in ethyl acetate. The organic solution was washed with water, dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography on silica, eluting with 0%-25% ethyl acetate in petroleum ether. The fractions containing the desired product were concentrated under vacuum to give the title compound (48 mg). LCMS m/z 306.02 [M+H]+ R.T.=11.48 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.5 (m, 3H), 7.4 (s, 1H), 7.3-7.4 (m, 2H), 3.6 (m, 4H), 1.7-1.5 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:34][CH3:35])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([OH:33])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:14])([F:15])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:34][CH3:35])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([O:33][CH2:43][C:44]([F:47])([F:46])[F:45])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(O)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OCC(F)(F)F)cnc12
Temperature: 40 °C
Yield: 36.1 %

Procedure:
tert-Butyl[(1R,2R)-2-({[5-ethyl-4-(6-hydroxypyrazolo[1,5-a]pyrimidin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (81.0 mg, 0.155 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (40.3 mg, 0.173 mmol), and potassium carbonate (27.9 mg, 0.202 mmol) were placed in a sealed tube and heated to 40° C. for 6 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with 1N NaOH (aq) once and 1N HCl (aq) twice. Water was added and the product extracted 3× with dichloromethane. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via column chromatography (0-100% EtOAc/Hex) to give the title compound (34.0 mg, 0.056 mmol). LRMS (APCI) calc'd for (C26H30F5N5O4S) [M+H]+, 604.2; found 604.0.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=O)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>C1COCC1>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([NH:32][CH2:33][CH2:34][CH2:35][N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)=[O:29])=[CH:30][CH:31]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)COc1ccc(OCc2ccccc2)cc1
Reactant: NCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(COc1ccc(OCc2ccccc2)cc1)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1′-Carbonyldiimidazole (16.2 g) was added to a stirred suspension of 4-benzyloxyphenoxyacetic acid (25.8 g) in dry THF (350 ml) and the mixture was stirred at ambient temperature for 2 hours. 1-(3-Aminopropyl)imidazole (12.5 g) was added and the mixture was stirred for a further 18 hours. The mixture was filtered and the filtrate evaporated to give a residue which was treated as in Example 9a to give 2-(4-benzyloxyphenoxy)-N-[3-(imidazol-1-yl)propyl]acetamide m.p. 112-113° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14]
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A solution of 2-bromo-1-(2-chlorophenyl)ethanone (7.55 g, 32.3 mmol) and potassium thiocyanate (3.14 g, 32.3 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 5.15 g (75.3%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][Br:17])[CH:3]=1
Reactant: Cc1cc(Cl)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1cc(Br)cc(CBr)c1
Temperature: 80 °C

Procedure:
Step G2. The mixture of 3-bromo-5-chlorotoluene (9 g, 43.8 mmol), NBS (8.19 g, 46 mmol), and AIBN (200 mg) in carbon tetrachloride (50 mL) was heated at 80° C. for 3 hours. The resulting mixture was run through a silicon gel column with dichloromethane as the eluant. The fraction was collected and solvent was removed by rotovap, crude 1-bromo-3-(bromomethyl)-5-chlorobenzene (3) was obtained as a brown residue and used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:4]=[N:3]1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][NH:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])[CH:4]=[N:3]1
Reactant: Cn1cc(CNCCCN)cn1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: Cn1cc(CN2CCCNC2=C[N+](=O)[O-])cn1
Yield: 70.1 %

Procedure:
A mixture of 16.8 g of N-(1-methyl-4-pyrazolylmethyl)-trimethylenediamine, 16.5 g of 1-nitro-2,2-bis(methylthio)ethylene and 200 ml of ethanol wash heated under reflux until the generation of methylmercaptan ceased. The mixture was cooled, and the precipitated crystals were collected by filtration. Washing with methanol gave 16.6 g of the desired 1-(1-methyl-4-pyrazolylmethyl)2-(nitromethylene)tetrahydropyrimidine as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 61 %

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 225, 30 g, 0.1 mol), Cs2CO3 (50 g, 0.15 mol) in DMF (150 mL), MeI (28.4 g, 0.2 mol) was added dropwise at 0° C. After addition, the mixture was stirred at room temperature for 10 hours. The reaction mixture was cooled to 0° C. and quenched by the addition of water (500 mL). Then the solid was collected by filtration and washed with Et2O (100 mL) to afford 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a brown solid in 61% yield, 20 g.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2].[CH3:35][C:36]1([CH3:42])[O:40][C:39](=[O:41])[N:38]=[CH:37]1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:38]3[CH2:37][C:36]([CH3:42])([CH3:35])[O:40][C:39]3=[O:41])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Reactant: CC1(C)C=NC(=O)O1
Product: CC(=O)N1CCN(c2cc(N3CC(C)(C)OC3=O)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Yield: 23.4 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (336 mg) described in Preparation Example 196 and 5,5-dimethyloxazolin-2-one (80.3 mg) described in Preparation Example 43, the title compound (91.3 mg) was obtained.
Reaction SMILES: Cl[CH:2]=[CH:3][CH2:4][SiH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]1[O:14][CH2:13]1.[Li]>>[CH:13]([O:14][CH:2]=[CH:3][CH2:4][SiH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:12]
Reactant: ClC=CC[SiH2]c1ccccc1
Reactant: C1CO1
Agent: [Li]
Product: C=COC=CC[SiH2]c1ccccc1
Yield: 68 %

Procedure:
Following the procedure of Example 21B, 98 mL (101.33 g, 0.555 mole) of (chloro)vinylmethylphenylsilane was added to the cooled lithium ethenoxide solution prepared in Part A. After work-up and distillation as described in Example 21B, there was obtained 65.21 g (68% yield) of (ethenyloxy)vinylmethylphenylsilane distilling at 78.8°/5.0° mm-80.0°/4.8 mm. The 1H NMR Spectrum (Cl3CD) exhibited resonances at δ=0.50 ppm (CH3 --Si), ~4.1 and 4.5 ppm (CH2 of vinyl on oxygen), a complicated multiline pattern at δ=5.7-6.6 ppm (vinyl group on silicon and the CH of the vinyl group on oxygen) and at δ=7.2-7.7 ppm (C6H5) with the relative intensities consistent with (ethenyloxy)vinylmethylphenylsilane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH2:26])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].Br.CC1C([C:35]2[NH:36][CH2:37][CH2:38][N:39]=2)=C(C)NN=1>CO>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH:26][C:35]3[NH:39][CH2:38][CH2:37][N:36]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCON)ccc21
Reactant: Cc1n[nH]c(C)c1C1=NCCN1
Agent: Br
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCONC3=NCCN3)ccc21
Reaction time: 120 h
Yield: 99 %

Procedure:
3-[5-(2-aminooxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethyl ester (208 mg, 0.56 mmol) and 2-(3,5-dimethylpyrazolyl)-4,5-dihydroimidazole hydrobromide (125 mg, 0.90 mmol) were dissolved in methanol (3 mL) and stirred for 5 days. The solvent was evaporated under vacuum and the crude mixture was purified via column chromatography with silica gel, eluting with 10% methanol in dichloromethane to afford the title compound (99% yield). 1H NMR (CDCl3) δ 7.16–7.29 (m, 7H), 7.07 (d, 1H, J=2.3 Hz), 6.80 (dd, 1H, J=2.3, 8.8 Hz), 6.47 (d, 1H, J=3.2 Hz), 6.00 (t, 1H, J=7.0 Hz), 4.24 (m, 2H), 4.17 (m, 2H), 4.03 (c, 2H, J=7.2 Hz), 3.51 (br s, 4H), 3.26 (m, 2H), 1.09 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:30][C:31](=[O:33])[CH3:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=[C:17]([CH:18]=[CH2:19])[C:10]=12>C(O)C.[Pd]>[CH2:18]([C:17]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:30][C:31](=[O:33])[CH3:32])=[CH:3][C:2]=2[F:1])[N:15]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH:16]=1)[CH3:19]
Reactant: C=Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2nccc(Oc3ccc(NC(C)=O)cc3F)c12
Agent: [Pd]
Solvent: CCO
Product: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2nccc(Oc3ccc(NC(C)=O)cc3F)c12

Procedure:
82 mg (0.18 mmol) of N-[3-fluoro-4-({1-[(4-methylphenyl)sulfonyl]-3-vinyl-1H-pyrrolo[2,3-b]-pyridin-4-yl}oxy)phenyl]acetamide are dissolved in 25 ml of ethanol. 19 mg (0.02 mmol) of 10% palladium-on-carbon are added, and the mixture is hydrogenated under a hydrogen atmosphere of 1.5 atm overnight. The mixture is then filtered through Celite® and the solvent is removed under reduced pressure. The product is reacted further without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:4]2[CH:5]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[O:26])[CH:20]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CCCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61A starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61A, Step 2) and pyrrolidine. LCMS (M+H)+: m/z=513.3.
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[N:9]=1)[CH3:4]>O.C1COCC1>[CH2:3]([C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)[CH3:4]
Reactant: CCOC(=O)c1csc(CC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide (1.405 g, 58.68 mmol) in water (13.75 mL) was sonicated for 10 min before being added to a stirred mixture of ethyl 2-ethylthiazole-4-carboxylate (2.78 g, 15.01 mmol) in THF (55 mL). The reaction was stirred art RT overnight. The solution was diluted with water and extracted with EtOAc (×3). The organic extracts were discarded. The aqueous was acidified with 2M HCl and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to give the sub-title compound as a brown oil which solidified on standing to give a waxy solid. Yield: 1.02 g
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2C1CCC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (142.5 mg, 0.4536 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (150.2 mg, 0.4533 mmol), Na2CO3 (120 mg, 1.13 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-12)→1% MeOH in CH2Cl2 (13-37)→2% MeOH in CH2Cl2 (38-61)], yielding the title compound as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ=1.88-2.00 (m, 2H), 2.44-2.56 (m, 2H), 2.56-2.65 (m, 2H), 5.27 (brs, 2H), 5.35 (quint, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.46-7.51 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.28-8.31 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=15.03 (−), 31.11 (2C, +), 48.26 (+), 101.15 (Cquart), 115.99 (Cquart), 118.99 (+), 120.86 (+), 125.97 (Cquart), 127.42 (+), 127.55 (2C, +), 128.26 (+), 128.48 (+), 128.87 (2C, +), 129.52 (+), 136.49 (Cquart), 136.55 (+), 139.43 (Cquart), 148.52 (Cquart), 150.79 (Cquart), 151.97 (+), 156.97 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (17) [MH+], 338.2 (22) [MH+-cyclobutene]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).