Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C1CCN2C(=NCCC2)CC1.[N+:34]([C:37]1[CH:38]=[C:39](/[CH:43]=[CH:44]\[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]>C(#N)C>[N+:34]([C:37]1[CH:38]=[C:39]([CH:43]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:44][C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#C/C=C\c1cccc([N+](=O)[O-])c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cccc([N+](=O)[O-])c4)c3)ncnc21
Temperature: 67 °C

Procedure:
To 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.500 g, 0.00158 mol) in 8.0 mL of dry ACN was added DBU (0.24 mL, 0.0016 mol) followed by addition of (2Z)-3-(3-nitrophenyl)acrylonitrile (0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction mixture was heated at 67° C. for 18 hours. This was cooled to room temperature, and the mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 6:4, to give 3-(3-nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as a dark orange oil, (688 mg, 88.65%). LCMS (M+1)+:490
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[F:25].CN1C(=O)N(C)CCC1.C(O[Li])(C)(C)C.[C:41]([CH2:45]OS(C(F)(F)F)(=O)=O)([F:44])([F:43])[F:42]>C1COCC1>[CH3:1][C@H:2]1[N:7]([CH2:45][C:41]([F:44])([F:43])[F:42])[C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[F:25]
Reactant: C[C@H]1NC(=O)C(NC(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Li]OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)CC(NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
To a solution of 46 (50 g, 0.14 mol) and DMPU (7.2 g, 0.06 mol) in THF (500 mL) was added tert-BuOLi (8.6 g, 0.11 mol) in portions at 20° C. for 0.5 h. After the mixture was degassed for 30 min at 20° C., CF3CH2OTf (37.5 g, 0.14 mol) was added at 20-25° C. The solution was stirred for 24 h at 20-25° C. After the reaction was complete, the mixture was quenched by water, and then partitioned with water and EtOAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (2-10% EtOAc/PE) to give product 47 (50 g, 82% yield). 1H (DMSO-d6, 400 MHz): δ 7.52 (m, 1H), 7.22-6.91 (m, 1H), 4.65 (m, 1H), 3.85 (br, 1H), 3.38-3.37 (m, 2H), 1.40 (s, 9H), 0.90 (m, 3H); MS (ESI) m/e [M+H]+: 441.15.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[Br:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:34](=[O:35])[CH2:33][Br:32])[C:4]=2[O:3][CH2:2]1
Reactant: c1ccc(Oc2ccccc2NCc2cccc3c2OCO3)cc1
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)N(Cc1cccc2c1OCO2)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of N-(benzo[1,3]dioxol-4-ylmethyl)-N-(2-phenyloxy-phenyl)amine (0.18 g, 0.58 mmol) dissolved in DCM (4 mL) was added triethylamine (0.24 g, 2.32 mmol, 0.32 mL). The reaction was cooled to 0° C. and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) was added. The mixture was stirred at room temperature for 2 h. LC-MS indicated starting material and product (1:1). Further triethylamine (0.24 g, 2.32 mmol, 0.32 mL) and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) were added and stirred at room temperature for 2 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with DCM (A) and MeOH (B) (1% B, 80 g, 2 CV, 60 mL/min). The impure product was further purified by silica gel chromatography eluting with DCM (A) and EtOAc (B) (1-5% B, 80 g, 4.5 CV, 60 mL/min) to afford 120 mg (47%) of N-(benzo[1,3]dioxol-4-ylmethyl)-2-Bromo-N-(2-phenyloxy-phenyl)acetamide as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)[CH3:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: CI
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCN(C)C(=O)OC(C)(C)C)ccc1F
Reaction time: 1 h

Procedure:
To a solution of [2-(4-fluoro-3-methoxyphenyl)ethyl]carbamic acid t-butyl ester (795 mg) in N,N-dimethylformamide (6 mL) was added 60% sodium hydride (154 mg) at room temperature. After stirring for 1 hour, methyl iodide (0.55 mL) was added dropwise and the solution was stirred for 14 hours. Water was added cautiously by small amounts, and after extraction with ethyl acetate, the solution was washed with water and saturated sodium chloride water. The residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (506 mg) was obtained as a colorless oily matter.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.Cl.[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([N:39]([CH3:41])[CH3:40])[CH:37]=2)[N:32]=[CH:31][CH:30]=1.O=[O+][O-]>O.CCO>[ClH:28].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([N:39]([CH3:41])[CH3:40])[CH:37]=5)[N:32]=[CH:31][CH:30]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Agent: Cl
Agent: O=[O+][O-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccc(N(C)C)cc45)cc3)cc2)nc(N)n1

Procedure:
To a solution of amide E5 (228 mg, 0.62 mmol) in 1:2 EtOH:H2O (20 mL) were sequentially added c.HCl (0.17 mL, 5.61 mmol) and 4-chloro-6-dimethylaminoquinoline (O3) (140 mg, 0.68 mmol), and the resulting mixture was refluxed for ˜12 h. MS and TLC analysis (eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:AcOH) after this time showed some starting material still present in the reaction mixture, thus more O3 (140 mg, 0.68 mmol) was added. After a further few hours refluxing, TLC showed the reaction was complete, and thus solvent was removed under reduced pressure. The residue was crystallized from MeOH:EtOAc to afford Cpd. P as an (extremely fine) amorphous yellow solid (170 mg, 51%). 1H NMR [(CD3)2SO] δ 2.28 [s, 3H], 3.15 [s, 6H, ArN(CH3)2], 6.21 [br s, 1H, ArH], 6.89 [d, J=6.71 Hz, 1H, ArH], 7.65 [m, 5H, ArH], 7.82 [m, 4H, ArH & ArNH2], 7.96 [d, J=9.39 Hz, 1H, ArH], 8.18 [d, J=8.57 Hz, 2H, ArH], 8.35 [t, J=12.38, 6.19 Hz, 1H, ArH], 10.44 [br s, 1H, ArH], 10.65 [br s, 1H, ArNHAr], 10.71 [s, 1H, ArNHAr], 12.75 [br s, 1H, ArC(O)NH], 14.56 [d, J=4.10
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1nccc(NCC2CC2)n1
Temperature: 25 °C
Yield: 64 %

Procedure:
In a microwave reaction vessel, slurry 2,4-dichloropyrimidine (0.5 g, 3.36 mmol), cyclopropylmethylamine (275 μL, 3.18 mmol), and diisopropylethylamine (1.17 mL, 6.72 mmol) in iso-propanol (2 mL). Irradiate in microwave (300 watts) at 130° C. for 15 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1 to 1:3 over 45 min; 40 mL/min) to obtain the desired intermediate (374 mg, 65%) as a colorless oil.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.[NH2:32][C@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34].Cl.C(N(CC)CC)C>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:2]([C:15]([NH:32][C@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[O:17])[CH2:3][CH2:4][C:5](=[O:14])[OH:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Boc-L-Glu(OBzl)OSu (Bachem, 434 mg (1 mmol) is reacted with L-Ala-OtBu.HCl, 182 mg (1 mmol) in 10 mL DMF containing triethylamine (202 mg). After stirring for 16 hours at room temperature, the reaction mixture is rotary evaporated to dryness and the residue is redissolved in methylene chloride, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is redissolved in methanol, 50 mL, and transferred to a Parr flask. 10% Pd/C catalyst (Aldrich), 50 mg, is added and the flask is charged with 40 psi hydrogen gas on a Parr shaker. The mixture is shaken for 2 hours at room temperature or until no further consumption of hydrogen is noted. The Parr flask is evacuated and charged with argon gas. The mixture is filtered through Celite, and the filtrate is rotary evaporated to give crude Boc-L-Glu-Ala-OtBu.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9](O)[N:4]2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([Cl:15])[N:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(N)nc2n1
Product: Cc1cc(Cl)n2nc(N)nc2n1

Procedure:
2-Amino-7-hydroxy-5-methyl-s-triazolo[1,5-a]pyrimidine (20 g) was suspended in 120 ml of phosphorus oxychloride under ice cooling, and the suspension was refluxed for two hours. Excess phosphorus oxychloride was removed by distillation under normal pressure. The 40 ml of reddish brown oil left was shaken with 300 ml of dichloromethane and 200 ml of water and the organic layer was collected. The aqueous layer was again extracted with 200 ml of fresh dichloromethane, and the combined organic extract was treated with saturated sodium bicarbonate solution until the pH of washings rose to 7 to 8, then washed with 100 ml of saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the dried solution was concentrated under reduced pressure to about 30 ml, and the concentrate was crystallized using 80 ml of n-hexane, affording 17 g of the objective compound as faint yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:12])[N:9]=2)[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)c2[nH]ncc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: Cc1ccc(Br)c2nn(C)cc12
Temperature: 80 °C

Procedure:
To a solution of 7-bromo-4-methyl-1H-indazole (1 equiv.) in acetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 equiv.) was added and reaction was heated at 80° C. for 1.5 h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2SO4 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOE experimentation).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(Cl)(Cl)Cl>[OH:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][OH:12])[CH2:19][CH2:20][CH2:21][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: NCCCN(CCO)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: OCCN(CCO)CCCNc1ccnc2ccccc12

Procedure:
A mixture of 5.0 g. of 4-chloroquinoline, 7.2 g. of bis(2-hydroxyethyl)aminopropylamine, 3.0 g. of sodium carbonate and 25 ml. of isopropanol is heated in a pressure vessel at 150° C. for 17 hours. The resulting mixture is diluted with chloroform, filtered and purified by filtering over silica gel to obtain an oil of 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.
Reaction SMILES: [OH:1][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:20][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:18]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:5]OC1.[O:33]1[CH2:38]CC(=O)[CH2:35][CH2:34]1>>[OH:1][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:18][CH:19]([C:21]4[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=4)[CH2:20]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:35][CH2:34][O:33][CH2:38][CH2:5]1
Reactant: O=C1CCOCC1
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(O)COC2)nc1C
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(O)CCOCC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 192, except dihydro-2H-pyran-4(3H)-one was used in place of oxetan-3-one. m/z (ES+) 457 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25]([N:27]3[CH2:31][CH2:30][S:29][CH2:28]3)=[O:26])[CH:15]=2)[CH:5]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCS(=O)C3)=[O:52])C=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25]([N:27]3[CH2:31][CH2:30][S:29](=[O:52])[CH2:28]3)=[O:26])[CH:15]=2)[CH:5]=[C:6]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])[CH:7]=1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Reactant: O=C(c1cc(-c2cc(F)cc(OCC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1
Agent: O=C(OO)c1cccc(Cl)c1
Product: O=C(c1cc(-c2cc(F)cc(OCC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCS(=O)C1

Procedure:
44 mg (0.10 mmol) of the compound of Example 72 is reacted analogously to the synthesis of the compound of Example 6 with 24 mg (0.10 mmol, 70%) of meta-chloroperbenzoic acid overnight at room temperature. The crude product is filtered over a Millipore spray filter and separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient). 35 mg (77% of theory) of the title compound is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.[Cl:27]C1C=C2C(=CC=1)NC(=O)C2>>[Cl:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:26])[C:17]2=[CH:16][C:12]1[CH:11]=[C:10]2[C:15]([C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:8][NH:9]2)=[CH:14][CH:13]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=C1Nc2ccccc2C1=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc2c(-c3cccnc3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of 3-((3-(pyridin-3-yl)-1H-indazol-6-yl)methylene)indolin-2-one, except substituting 5-chlorooxindole (5.3 mg, 0.031 mmol) the title compound was prepared as a yellow solid (6.5 mg, 54%). A mixture of (E)- and (Z)-isomers (68:32 by NMR) was obtained. 1H NMR (400 MHz, d6-DMSO) δ 13.77 (br s, 1H), 10.80 (br s, 1H), 9.24 (d, J=1.5 Hz, 1H), 8.63 (dd, J=4.8, 1.8 Hz, 1H), 8.41 (dt, J=7.8, 1.8 Hz, 1H), 8.28 (d, J=8.5 Hz, 1H), 8.21-8.16 (m, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.57 (t, J=4.5, 1H), 7.55-7.52 (m, 1H), 7.31 (dd, J=8.3, 2.3 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H); MS ESI 373.1 [M+H]+, calcd for [C21H13ClN4O+H]+ 373.08.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1
Reactant: C1=COCCC1
Reactant: O=C1COc2ccc(CO)cc2N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1COc2ccc(COC3CCCCO3)cc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The solution of 5.0 g of 6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one in 60 ml of dichloromethane is admixed successively with 5.20 ml of 3,4-dihydro-2H-pyran and 0.236 g of p-toluenesulphonic acid monohydrate. The reaction mixture is stirred at room temperature over 14 hours. The solution is poured onto 1M sodium hydrogencarbonate solution (300 ml) and extracted with tert-butyl methyl ether (2×400 ml). The organic phase is washed with brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of crystallization (EtOAc/heptane). Rf=0.25 (1:1 EtOAc-heptane); Rt=3.45.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)[NH2:2].[CH3:15][C:16]([CH3:23])([CH3:22])[C:17](=O)[CH2:18][C:19]#[N:20].Cl>CCO>[NH2:20][C:19]1[N:1]([C:3]2[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=2)[N:2]=[C:17]([C:16]([CH3:23])([CH3:22])[CH3:15])[CH:18]=1
Reactant: CCOC(=O)Cc1cccc(NN)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 91.9 %

Procedure:
A solution of ethyl (3-hydrazinophenyl)acetate (15 g, 65 mmol) and 4,4-dimethyl-3-oxopentanenitrile (12.5 g, 0.1 mol) in EtOH (100 mL) containing conc. HCl (25 mL) was heated at reflux overnight. After removal of the solvent, the residue was washed with Et2O to afford ethyl 2-(3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl)acetate (18 g). MS (ESI) m/z: 302 (M+H+).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11]O>CCOCC.C(Cl)Cl>[Br:2][CH2:11][C:10]1[O:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:6]=1[CH3:5]
Reactant: BrP(Br)Br
Reactant: Cc1nc(-c2ccccc2)oc1CO
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)oc1CBr
Reaction time: 4 h

Procedure:
80 mL (0.67 mmol) of PBr3 is added slowly to a solution of 104 mg (0.57 mmol) of (4-methyl-2-phenyl-oxazol-5-yl)-methanol in 0.5 mL of Et2O and 1.5 mL of CH2Cl2 at 0° C. The coolin bath is removed, and the reaction mixture is stirred for 4 h. The reaction mixture is then partitioned between saturated aqueous NaHCO3 solution and Et2O. The organic phase is separated and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to produce 5-bromomethyl-4-methyl-2-phenyl-oxazole as a solid; 1H NMR (250 MHz, CDCl3) δ7.90-7.99 (m, 2H), 7.32-7.40 (m, 3H), 4.50 (s, 2H), 2.16 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21].[CH3:23][S:24]([CH:27]=[CH2:28])(=[O:26])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[N:4]([CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[C:3]1=[O:21]
Reactant: C=CS(C)(=O)=O
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccncc3F)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCS(C)(=O)=O)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
To a solution of N-(3,3-dimethyl-2-oxoindolin-6-yl)-3-fluoroisonicotinamide (example 72, 100 mg, 334 μmol) in DMF (1.67 ml) under an argon atmosphere was added methylsulfonylethene (35.5 mg, 31.6 μl, 334 μmol) and cesium carbonate (109 mg, 334 μmol). After 3 hours at room temperature the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent followed by preparative HPLC. The title compound was obtained as off-white solid (60 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]([NH2:36])([C:34]#[CH:35])[CH3:33]>>[NH2:36][C:32]([CH3:33])([CH3:31])[C:34]#[C:35][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[C:20]([OH:22])=[O:21])=[C:9]2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(C)(C)N
Product: Cc1cc2ccc(C#CC(C)(C)N)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-(7-(3-Amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (85) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 2-methylbut-3-yn-2-amine. 1H-NMR: 400 MHz, (CD3OD) δ: 7.81 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.57 (m, 3H), 7.45 (d, J=8 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.62 (s, 3H), 1.68 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M—NH2]+ calcd for C28H28ClO3: 447.2; found: 446.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:15]=[C:14]2[CH:16]=[CH:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]2=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]1[N:15]=[C:14]2[CH:16]=[CH:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]2=[CH:12][CH:11]=1)[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(ccn2C(=O)OC(C)(C)C)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(Cc1ccc2c(ccn2C(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a stirred solution of tert-butyl 5-[(tert-butoxycarbonylamino)methyl]-pyrrolo-[3,2-b]pyridine-1-carboxylate (360.0 mg, 1.036 mmol) and iodomethane (0.065 mL, 1.036 mmol) in anhydrous THF (6.3 mL) cooled to −40° C. was added dropwise lithium bis(trimethylsilyl)amide in THF (1.24 mL, 1.24 mmol, 1M). The reaction mixture was warmed to 0° C. and stirred at 0° C. for 1 h. The reaction was quenched with water and then diluted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with a mixture of EtOAc containing 1% TEA and heptane to afford 130.0 mg (37.3%) of tert-butyl 5-((tert-butoxycarbonyl(methyl)amino)methyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate as a foam: 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=7.6 Hz, 1H), 7.82 (d, J=3.5 Hz, 1H), 7.27-7.10 (m, 1H), 6.73 (d, J=3.7 Hz, 1H), 4.64 (s, 2H), 3.02-2.82 (m, 3H), 1.68 (s, 9H), 1.56-1.41 (m, 9H); MS (ESI) m/z: 362.3 [M+1]+