Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:17])=[CH:10][C:11]=3[C:12]2([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH2:18]([OH:22])[CH2:19][C:20]#[CH:21].O.Cl>C1COCC1.C(NC(C)C)(C)C.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.[Cu]I>[OH:22][CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:17])=[CH:10][C:11]=3[C:12]2([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: CC1(C)c2cc(O)ccc2-c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)c2cc(O)ccc2-c2ccc(C#CCCO)cc21

Procedure:
14.7 g (0.048 mol) of 7-bromo-9,9-dimethyl-9H-fluoren-2-ol, 1.3 g (1.85 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.5 g (2.6 mmol) of copper(I) iodide are initially introduced in 200 ml of THF and 20 ml of diisopropylamine, and a solution of 9.5 ml (0.13 mmol) of but-3-yn-1-ol in 50 ml of THF is added over the course of 2 h under reflux. When the addition is complete, the batch is heated under reflux for a further 1 h, added to water, acidified using dil. hydrochloric acid and extracted three times with ethyl acetate. The combined org. phases are dried over sodium sulfate, and the solvent is removed in vacuo. Chromatography of the crude product on silica gel with toluene/ethyl acetate (4:1) gives 7-(4-hydroxybut-1-ynyl)-9,9-dimethyl-9H-fluoren-2-ol as colourless oil.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].C(C1(C2C=CC(OC)=C(C=2)[CH:27]=[O:28])CC1)#N>>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:10]=2)[CH:27]=[O:28])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COc1ccc(C2(C#N)CCCCC2)cc1C=O

Procedure:
This compound was prepared from 4-(1-Cyanocyclohexyl)anisole in the same manner of Compound 2.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)(=O)=O.[C-:23]#[N:24].[Na+].CS(C)=O>O>[C:23]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)#[N:24]
Reactant: [C-]#N
Reactant: CCCCCOc1ccc(-c2cnc(S(C)(=O)=O)nc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCOc1ccc(-c2cnc(C#N)nc2)cc1
Yield: 43.6 %

Procedure:
This compound (XI) (1.8 g, 0.006 mol) and NaCN (0.275 g, 0.006 mol) were added to dimethylsulfoxide (5 ml), followed by mixing at 100° C. for one hour, allowing the resulting material to cool, adding water (15 ml), filtering off the resulting crystals and recrystallizing crystals from ethanol to obtain 2-cyano-5-(4-pentyloxyphenyl)pyrimidine (XII) (0.7 g) (yield: 47%) having a melting point of 100° C.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:34]2[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][C:26]3[CH:27]=[CH:28][C:23]([S:22][CH3:21])=[CH:24][CH:25]=3)[CH2:36][CH2:35]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: CSc1ccc(CCN2CCNCC2)cc1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Product: CSc1ccc(CCN2CCN(C(=O)c3ccc(N(CCOC(C)C)C(=O)CCl)cc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.95 g of [2-(4-methylmercaptophenyl)ethyl]piperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-methylmercaptophenyl)ethyl]piperazine. The hydrochloride thereof melts at 115°-116°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])(C)(C)C>C1(C)C=CC=CC=1.C1COCC1>[C:9]([C:8]([CH3:12])([CH3:11])[C:4]1[CH:3]=[C:2]([B:13]([OH:18])[OH:14])[CH:7]=[CH:6][CH:5]=1)#[N:10]
Reactant: CC(C)(C#N)c1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 120.2 %

Procedure:
A solution of 2-(3-bromo-phenyl)-2-methyl-propionitrile [0.5 g, 2.2 mmol, Intermediate (65)] in toluene (8 mL) and THF (2 mL) is added triisopropyl borate (0.61 mL, 2.68 mmol) at −78° C. tert-Butyl lithium (1.7 M in pentane, 1.55 mL, 2.68 mmol) is added dropwise during 15 min. Reaction mixture is stirred at −78° C. for additional 1 hour, warmed up to −20° C. and quenched with 2 N hydrochloric acid (10 mL). The reaction mixture is extracted with ether, combined ether layers are washed with brine, dried and concentrated to obtain 3-(cyano-dimethyl-methyl)-phenyl boronic acid (0.5 g) [Intermediate (66)] as an oil.
Reaction SMILES: [I-].C[S+](C)C.[CH2:6]([Li])CCC.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:23][C:24]3[CH:25]=[C:26]([CH:30]4[O:34][CH2:33][CH2:32][O:31]4)[CH:27]=[CH:28][CH:29]=3)=[N:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]3[CH2:6][CH:23]3[C:24]3[CH:25]=[C:26]([CH:30]4[O:34][CH2:33][CH2:32][O:31]4)[CH:27]=[CH:28][CH:29]=3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc2ccc(C=Cc3cccc(C4OCCO4)c3)nc2c1
Reactant: [Li]CCCC
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: Clc1ccc2ccc(C3CC3c3cccc(C4OCCO4)c3)nc2c1
Temperature: 21 °C
Reaction time: 8 h

Procedure:
To a solution of trimethylsulfonium iodide (2.128 g, 10.4 mmoles) in 20 mL of anhydrous THF at -10° C. was added dropwise a solution of n-butyllithium 1.6M in hexanes (4.9 mL, 0.75 equiv.). Then the temperature was raised to 21° C. for 2 hours. To this mixture cooled to 0° C., the alkene (step 2) (967 mg, 2.86 mmoles) in 5 mL THF was added and the solution stirred overnight. Hydrolysis with 25% aqueous NH4OAc, extraction with EtOAc and flash chromatography on silica using EtOAc:toluene 2.5:97.5 afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].O1CCCC1.BrCCCCl>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]12[CH2:7][N:8]([CH2:9][CH2:10][CH2:11]1)[CH2:12][CH2:20][CH2:19]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[N-]C(C)C
Agent: ClCCCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C12CCCN(CCC1)C2
Temperature: -35 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A cooled (-50° C.) solution of 1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-ethyl ester (12.9 g, 50 mmol) in anhydrous tetrahydrofuran (60 mL) was treated (via syringe) with 1.15N lithium diisopropylamide/tetrahydorfuran (52 mmol), stirred for one hour at -15°±5° C., cooled (-35° C.), treated with 1-bromo-3-chloropropane (10.2 g, 65 mmol), warmed to room temperature over one hour, and stirred for 30 minutes. Most of the solvent was removed in vacuo, replaced with ether, and the organic solution was washed with saturated sodium bicarbonate (150 mL). The aqueous solution was extracted with ether (2×50 mL), and the combined organic solution was dried (MgSO4), concentrated in vacuo, and passed through a short column of alumina (eluted with methylene chloride). The concentrated filtrate was dissolved in anhydrous methylene chloride (25 mL), cooled (10° C.), and treated dropwise with trifluoroacetic acid (15 mL). The solution was stirred for one hour at room temperature, 15 minutes at 45° C., and concentrated in vacuo. The residue was partitioned between 1.25N sodium carbonate (75 mL) and methylene chloride (100 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo, taken up in warm hexane, treated with a little charcoal, and filtered. The filtrate was concentrated in vacuo and the residue was distilled (bp 0.6 83°-85° C.) to give 7.2 g (73%) of the product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.N1C=NN=N1.C(N(CC)[P:21]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])C.[OH:34]O>C(#N)C.C(Cl)Cl>[C:28]([O:27][P:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:34])([CH3:29])([CH3:30])[CH3:31]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Reactant: OO
Agent: c1nnn[nH]1
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OP(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a stirred solution of methyl 2-(4-hydroxyphenyl)acetate (1.80 g, 10.83 mmol) in acetonitrile (35 mL) was added 1H-tetrazole (3% 1H-tetrazole in MeCN, 65.0 mL, 22.1 mmol), followed by di-tert-butyl diethylphosphoramidite (5.91 g, 23.70 mmol). The reaction mixture was stirred at room temperature for 35 min and concentrated to give a solid. To this solid in 50 mL of DCM was added 30% H2O2 (30 mL). The resulting mixture was stirred at room temperature for 30 min and diluted with DCM. The organic phase was separated, washed sequentially with water, saturated NaHCO3 solution, and brine, then concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc) to afford Preparation 44B (3.94 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.25-7.14 (m, 4H), 3.69 (s, 3H), 3.59 (s, 2H), 1.51 (s, 18H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)CC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (49 mg, 70%), MS (ISP) m/z=441.4 [(M+H)+], mp 216.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 3,3,3-trifluoropropanoic acid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[CH3:19][C:20](=[O:23])[CH:21]=C.[CH2:24]([N:26]1[C:38]2[CH:37]=[CH:36][C:35]([NH2:39])=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:25]>>[C:14]([CH:13]=[C:11]1[CH2:12][N:8]([CH2:6][CH2:19][C:20](=[O:23])[CH3:21])[C@H:9]([C:16]([NH:39][C:35]2[CH:36]=[CH:37][C:38]3[N:26]([CH2:24][CH3:25])[C:27]4[C:32]([C:33]=3[CH:34]=2)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:18])[CH2:10]1)#[N:15]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Reactant: C=CC(C)=O
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CC#N)CN3CCC(C)=O)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, 3-buten-2-one, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 59% purity by LC/MS. MS(ESI+): m/z=415.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7](=[O:9])[CH3:8].[BH4-].[Na+]>CO.O.CC(O)=O>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH3:8]
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a mixture of 1-(2-methoxy-4-nitrophenoxy)propan-2-one (300 mg, 1.33 mmol) in 1.3 mL of MeOH and 1.3 mL of H2O at rt was added a solution of NaBH4 (53 mg, 1.40 mmol) in 0.5 mL of H2O dropwise over 5 min. The suspension was stirred at rt for 1 h and diluted with 0.2 mL of HOAc followed by 2 mL of H2O. The precipitate was filtered, washed with H2O and dried under vacuum to afford the title compound (270 mg) as a yellow solid. 1H NMR (CDCl3) δ 1.28 (d, J=6.05 Hz, 3H), 2.68, (s, 1H), 3.87-3.92 (m, 4H), 4.03-4.05 (m, 1H), 4.23-4.29 (m, 1H), 6.89 (d, J=9.35 Hz, 1H), 7.72 (d, J=2.20 Hz, 1H), 7.86 (dd, J=8.80 Hz, 2.75 Hz, 1H); 13C NMR (CDCl3) δ 18.66, 56.19, 65.90, 74.84, 106.73, 111.66, 117.60, 141.79, 149.21, 153.62; HPLC (Method # 1) 2.29 min retention time, (100%); LCMS (ES): m/z 228 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([CH3:36])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH3:37][S:38]([CH3:40])=O.C(OC(=O)C)(=O)C>O>[CH3:36][C:34]1[N:35]=[C:9]2[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:37][S:38][CH3:40])[CH2:3][CH2:4]3)[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]2[N:33]=1
Reactant: CS(C)=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCSC)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.5 g), dimethyl sulfoxide (45 mL) and acetic anhydride (15 mL) was stirred at room temperature for 17 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.83 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[N:4][C:3]=1Cl.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH3:27])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[N:4][C:3]=1[C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([Cl:25])[C:19]=1[Cl:18]
Reactant: Cn1nccc1C(=O)Nc1cnc(Cl)c(N)n1
Reactant: COc1cc(Cl)c(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Cl)c(Cl)c(-c2ncc(NC(=O)c3ccnn3C)nc2N)c1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
N-(6-Amino-5-chloropyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Preparation 2, 0.1 g, 0.396 mmol) was combined with 2,(2,3-dichloro-5-methoxy-phenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 18), (0.156 g, 0.515 mmol), cesium carbonate (0.129 g, 0.396 mmol) and palladium tetrakistriphenylphosphine (0.046 g, 0.04 mmol) and suspended in a mixture of 1,4-dioxane (1 ml) and water (0.5 ml). The reaction was heated at 80° C. for 5 hours. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The residue was partitioned between aqueous sodium carbonate solution (20 ml) and ethyl acetate (20 ml) and the organic layer dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:heptane 2:3 to 1:1, to afford the product as an off-white solid (72 mg).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10](Br)[C:11]#[CH:12].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]=[O:18]>C1COCC1.[Zn]>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]([OH:18])[CH2:12][C:11]#[CH:10]
Reactant: C#CCBr
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C#CCC(O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
General Procedure BB: To a mixture of zinc (0.60 g, 9.2 mmol) in THF (1 mL) was added 1,2-Dibromoethane (0.03 mL, 0.3 mmol). The resulting mixture was stirred under reflux for 15 min and then cooled to rt. To the reaction mixture was added TMSCl (0.03 mL, 0.2 mmol) and THF (5 mL). A solution of propargyl bromide (0.750 mL, 8.42 mmol) and THF (3 mL) was then added dropwise to the reaction mixture over a 30 min period at −10° C. After 1 h, 2,6-Dichlorobenzaldehyde (1.46 g, 8.33 mmol) was added to the reaction mixture and allowed to warm to rt and stirred for 36 h. The reaction mixture was quenched with 1 M aqueous HCl (15 mL) and the organic layer was washed with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield a dark yellow oil. The crude product was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to yield the desired product as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ=2.03-2.06 (m, 1H), 2.82-2.90 (m, 1H), 3.00-3.07 (m, 1H), 3.09 (d, J=9.1 Hz, 1H), 5.67 (td, J=8.8, 6.6 Hz, 1H), 7.14-7.21 (m, 1H), 7.32 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9]Br.Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+]>O1CCOCC1>[C:12](=[O:13])([O:14][CH3:15])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[Br:9]
Reactant: Oc1ccc(F)cc1
Reactant: BrBr
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)Oc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A stirred solution of 561 g (5.0 moles) of 4-fluorophenol in 600 mL of dioxane was cooled in an ice-water bath and 831 g (5.2 moles) of bromine was added dropwise. The complete addition required 1.5 hours, during which the reaction mixture temperature was maintained at 14°-25° C. Following the addition, the ice-water bath was removed, and the reaction mixture temperature rose to 35° C. The reaction mixture was stirred for two hours, then 600 mL of water, followed by 420 mL of 10.8N aqueous sodium hydroxide were added dropwise over 30 minutes and 1 hour respectively. Upon complete addition, the reaction mixture was cooled to 0°-10° C., and 591 g (6.15 moles) of methyl chloroformate was added dropwise over four hours. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature and was stirred for 17 hours. After this time, 450 g of aqueous 50% sodium hydroxide was added to neutralize the reaction mixture. The resultant solid was collected by filtration, and the filter cake washed with two 500 mL portions of water. The solid was dried under reduced pressure to give 1211 g of 2-bromo-4-fluorophenyl methyl carbonate; m.p. 75°-78° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[F:83][C:84]([F:95])([F:94])C1C=CC(B(O)O)=CC=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:3]=[CH:2][C:43]([C:84]([F:95])([F:94])[F:83])=[CH:42][CH:41]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 12 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-trifluoromethylphenylboronic acid (50 mg, 0.2625 mmol) to produce the title compound (14 mg, 12% yield).
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[NH2:7][C:8]1[NH:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:9]=1.[OH-].[K+]>>[NH2:1][N:12]1[C:8]([NH2:7])=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:11]1
Reactant: NOS(=O)(=O)O
Reactant: Nc1cc(-c2ccc(F)cc2)n[nH]1
Agent: [K+]
Agent: [OH-]
Product: Nc1cc(-c2ccc(F)cc2)nn1N
Temperature: 80 °C
Yield: 14.9 %

Procedure:
Hydroxylamine-O-sulfonic acid (2.26 g, 20-0 nmol) was portionwise added to aqueous solution, (100 mL) containing 5-amino-3-(4-fluorophenyl)-1H-pyrazole (2.0 g, 11.3 mmol) and potassium hydroxide (2.52 g, 45 mmol) while stirring at 80° C. After the mixture was stirred at 80° C. for 30 minutes, potassium hydroxide (2.52 g, 45 mmol) was added thereto, hydroxylamine-O-sulfonic acid (2.26 g, 20.0 mmol) was portionwise added, and the mixture was stirred for further 1 hour. The reaction solution was cooled down to room temperature, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous potassium carbonate, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (C-300, hexane:ethyl acetate=1:2) to obtain the title compound (324 mg, 14.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:35][C:36]([F:48])([F:47])[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44](Cl)=[O:45])=[O:38].C(Cl)Cl>CN(C1C=CN=CC=1)C.CCN(CC)CC>[F:48][C:36]([F:35])([F:47])[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@@H:40]1[C:44]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:45])=[O:38]
Reactant: O=C(Cl)C1CCCN1C(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)[C@H]5CCCN5C(=O)C(F)(F)F)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (20 mg, 0.044 mmol) and 1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carbonyl chloride (880 μL, 0.088 mmol, 0.1M solution in CH2Cl2) was added Et3N (12 μL, 0.088 mmol), catalytic amount of DMAP, and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of 1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carbonyl chloride and Et3N were added. Continued to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-((R)-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (130 mg, 46%)