Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[N:25]1([C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[N:26]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([N:25]5[CH:29]=[CH:28][CH:27]=[N:26]5)[CH:35]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(-n5cccn5)c4)cc23)CC1
Yield: 10 %

Procedure:
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20 mg, 0.048 mmol) was added [3-(1H-pyrazol-1-yl)phenyl]boronic acid (36 mg, 0.193 mmol), dioxane (2.8 mL) and a solution of potassium carbonate (20 mg) in water (1.2 mL). To this mixture was added chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (3 mg, 0.005 mmol). The resulting mixture was reacted in a CEM microwave for 10 min at 160° C. then concentrated under a stream of nitrogen (greenhouse) at 80° C. The crude product was partitioned between water (2 mL) and CH2CL2 (2 mL). The layers were separated with a hydrophobic frit, and the aqueous layer was extracted with CH2CL2 (2×2 mL). The organic layers were pooled and concentrated under a stream of nitrogen at 80° C. Dimethyl sulfoxide (0.8 mL) was added to residue, which was sonicated for 10 sec. filtered through a cotton plug, and then filtered through a 0.2 μm filter. The crude product was purified on an Agilent MDAP using a Zorbax Eclipse XDB 610 21.2×50 mm column to afford 2.3 mg of the title compound (10%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:29][Si](C)(C)C.BrN1C(=O)CCC1=O>C1COCC1>[Br:29][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: C[Si](C)(C)Br
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Br)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Commercially available methyl 2-(1-tert-butoxycarbonyl-4-piperidinyl)-acetate (Astatech, 2.57 g, 10.0 mmol) was dissolved in anhydrous THF (20 mL) under argon, cooled to −78° C., treated dropwise with a 1N solution of LHMDS in THF (20 mL), and stirred under positive Ar pressure for 30 mins. Bromotrimethylsilane (2.10 mL, 15.9 mmol) was added dropwise via dry syringe over 5 mins, then a solution of freshly recrystallized N-bromosuccinimide (2.14 g, 12.0 mmol) in anhydrous THF (20 mL) was added in one portion from an addition funnel. The reaction was kept at −78° C. for 2 hrs then warmed to ambient temperature. The crude reaction was concentrated in vacuo then partitioned between saturated aq. NaHCO3 and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and filtrate concentrated in vacuo giving 4.7 g of orange slurry. This was purified by flash column chromatography on silica gel (0 to 10% EtOAc/DCM step gradient elution), and the combined TLC-pure fractions were concentrated and dried in vacuo giving the title compound as a viscous, pale yellow oil. 1H NMR (CHLOROFORM-d) δ: 4.05-4.26 (m, 2H), 4.02 (d, J=8.8 Hz, 1H), 3.79 (s, 3H), 2.70 (br. s., 2H), 1.97-2.10 (m, 4H), 1.57-1.68 (m, 2H), 1.45 (s, 9H), 1.13-1.32 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:10]([O-])=O.[Na+].[Sn](Cl)Cl>O.Cl>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][NH2:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1c(F)cccc1NN
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
24 g 3-Fluoro-2-methyl-aniline was added to 120 ml 25% hydrochloric acid and the mixture cooled to 0° C. A solution of 15 g sodium nitrite in 80 ml water was added dropwise to the resulting suspension at such a rate that the temperature did not rise above 8° C. When the addition was complete, the mixture was stirred 1 h at 0° C. Whilst maintaining the mixture at 0° C., a suspension of 195 g tin (II) chloride in 230 ml 25% aqueous hydrochloric acid was added over 30 min. The mixture was stirred a further 20 min, and the precipitate that formed was filtered. The crude hydrochloride salt was partitioned between water and dichloromethane, and the pH raised to pH8 by the addition of sodium hydroxide solution followed by saturated sodium bicarbonate solution. The phases were separated, the aqueous phase extracted twice with dichloromethane and the combined organic phases dried over sodium sulfate and evaporated. The resulting solid residue was recrystallised from hexane to afford the title compound as a light brown solid (9.2 g, 34% yield, mp 69° C.; EI-MS m/e: 140.1 (M+)).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22]([OH:24])=[O:23])=[C:9]1[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36]O>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22]([O:24][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([F:41])=[C:33]([F:32])[CH:34]=2)=[O:23])=[C:9]1[CH:25]([CH3:26])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Reactant: OCc1ccc(F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(C(=O)OCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure E,1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 39 mg, 0.1 1 mmol) in CH2Cl2 (4 ml) was added EDC (35 mg, 0.22 mmol) and DMAP (16 mg, 0.15 mmol), followed by 3,4-difluorobenzyl alcohol (20 mg, 0.15 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: BrBr.C(OC(NC1C(Br)=CC(C(=O)C)=CC=1C)=O)C.Br.C(OC(NC1C(Br)=CC(C(=O)CBr)=CC=1C)=O)C.C(N)(C)(C)C.[CH2:44]([O:46][C:47]([NH:49][C:50]1[C:55]([Br:56])=[CH:54][C:53]([C:57](=[O:64])[CH2:58][NH:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[CH:52][C:51]=1[CH3:65])=[O:48])[CH3:45].N.[ClH:67]>C(Cl)(Cl)Cl.O>[ClH:67].[CH2:44]([O:46][C:47]([NH:49][C:50]1[C:55]([Br:56])=[CH:54][C:53]([CH:57]([OH:64])[CH2:58][NH:59][C:60]([CH3:62])([CH3:61])[CH3:63])=[CH:52][C:51]=1[CH3:65])=[O:48])[CH3:45]
Reactant: CCOC(=O)Nc1c(C)cc(C(=O)CNC(C)(C)C)cc1Br
Agent: Br
Agent: BrBr
Agent: CCOC(=O)Nc1c(C)cc(C(=O)CBr)cc1Br
Solvent: O
Solvent: CC(C)(C)N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1c(C)cc(C(O)CNC(C)(C)C)cc1Br

Procedure:
6.5 gm of bromine were added dropwise into a boiling solution of 12 gm of 4'-ethoxycarbonylamino-5'-bromo-3'-methyl-acetophenone in 200 ml of chloroform, whereupon hydrobromic acid was rapidly formed. The solution obtained, containing 4'-ethoxycarbonylamino-5', 2-dibromo-3'-methyl-acetophenone, was admixed with 14.6 gm of tert. butylamine. After refluxing for 30 minutes, the resulting solution containing 4'-ethoxycarbonylamino-5'-bromo-3'-methyl-2-tert. butylamino-acetophenone was evaporated in vacuo. The residue was dissolved in 50 ml of methanol and 20 ml of water. Reduction was effected by addition thereto of a solution of 3.8 gm of sodium borohydride in 20 ml of water with simultaneous adjustment of the pH to between 6 and 8 by addition of dilute hydrochloric acid. After reduction was complete, the methanol was distilled off in vacuo. The residue obtained was admixed with water, and the resulting solution was made alkaline by addition of liquid ammonia and extracted with chloroform. The organic phase was separated, dried and evaporated in vacuo. The evaporation residue was purified on a silicagel column (eluant: chloroform/methanol 2:1). After evaporation, the residue was dissolved in ethanol, and the solution obtained was admixed with ethereal hydrochloric acid to yield 1-(4-ethoxycarbonylamino-5-bromo-3-methyl-phenyl)-2-tert. butylamino-ethanol hydrochloride.
Reaction SMILES: [CH:1]1([C:4]#[N:5])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1>C1COCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:1]2([C:4]#[N:5])[CH2:3][CH2:2]2)=[N:18][CH:19]=1
Reactant: Fc1ccc(F)nc1
Reactant: N#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
Cyclopropanecarbonitrile (815 mg) was dissolved in THF (15 ml) and the solution cooled to 0° C. before dropwise addition of 0.9 M KHMDS (14.0 ml). The reaction mixture was allowed to warm to room temperature and stirred for further 15 min. The resulting solution was then added dropwise to a solution of 2,5-difluoropyridine (1.52 g) in THF (15 ml) and the reaction mixture stirred for 1 hour. Reaction was quenched by addition of aqueous NH4Cl, stirred for 5 min and then the organics washed with NaHCO3 and brine and dried over Na2SO4. The mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (SiO2; gradient: heptane/EtOAc) to give title compound as a white solid (880 mg). MS (ISP): 163.2 ([M+H]+)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Cl[CH2:17][C:18]([NH2:20])=[O:19]>O.C(O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:17][C:18]([NH2:20])=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: NC(=O)CNc1ccc([N+](=O)[O-])cc1
Yield: 58 %

Procedure:
A mixture of p-nitroaniline (55.2 g, 0.4 mol), calcium carbonate (80 g) and chloroacetamide (149.6 g, 1.6 mol) in 350 ml of water/ethanol (1/1) was refluxed for 42 hours. The resulting mixture was filtered while hot and allowed to cool, and the crystals were filtered off by suction, reslurried in water and then washed with absolute ethanol. After drying, 87.9 g of crude product were obtained. After two recrystallizations from acetonitrile, 45.3 g of pure product were obtained (melting point=178° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[C:30]1(=O)[CH2:34][CH2:33][C:32](=[O:35])[CH2:31]1.C([BH3-])#N.[Na+].CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:30]4[CH2:34][CH2:33][C:32](=[O:35])[CH:31]=4)[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: O=C1CCC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5=CC(=O)CC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (43 mg, 0.1 mmol), cyclopentane-1,3-dione (89 mg, 9.1 mmol), sodium cyanoborohydride (19 mg, 0.3 mmol) and DIEA (0.2 mL, 11 mmol) in MeOH (1 mL) was stirred in a sealed vial at 60° C. After 2.5 h, additional sodium cyanoborohydride (19 mg, 0.3 mmol) was added and the reaction continued to stir at 60° C. overnight. The mixture was purified by RP-HPLC to give 3-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)cyclopent-2-en-one as an off white solid; 1H NMR (400 MHz, DMSO-d6) δ 9.97 (br s, 1H), 9.83 (br s, 1H), 8.90 (s, 1H), 8.32 (d, J=6.8 Hz, 1H), 7.88 (d, J=12.8 Hz, 1H), 6.97 (s, 1H), 6.04 (s, 1H), 5.30 (br s, 1H), 4.71 (d, J=12.0 Hz, 2H), 4.04 (t, J=12.4 Hz, 2H), 3.84 (m, 1H), 3.53 (m, 2H), 3.13 (m, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 2.59-2.40 (m, 4H); ESMS m/z 496.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]([O-:13])=O)[N:8]([CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[Li+].C(Cl)(=O)C(Cl)=O.[CH3:22][N:23](C=O)[CH3:24].N(C)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]([N:23]([CH3:24])[CH3:22])=[O:13])[N:8]([CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: Cn1c(C(=O)[O-])cc2c(Cl)ncnc21
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2c(Cl)ncnc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
A reaction mixture containing carboxylate 275 (78 mg, 0.36 mmo), oxalyl chloride (63 uL, 0.72 mmol), and a drop of DMF in DCM was stirred for 2 h. Solvents were removed under reduced pressure and the residue was re-dissolved in DCM (4 mL). To this solution Me2NH (360 μL, 0.72 mmol, 2M in THF) in THF was added and the mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (eluent EtOAc) to afford the title compound 276 (50 mg, 58% yield) as a yellowish solid. MS (m/z): 239.1(M+H) (found).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([NH:34][CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: NC1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC4CCOCC4)c3)n2)n1
Yield: 87.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.465 g, 0.951 mmol) by treatment with commercially available 4-aminotetrahydropyran [CAS-no. 38041-19-9] (0.192 g, 1.9 mmol) in THF (5 ml) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.460 g, 87%) as an off-white solid. MS (ISP) 554.2 [(M+H)+]; mp 163° C. (dec.).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl>N1C=CC=CC=1>[CH:1]1([O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1OC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1OC1CCCCC1
Temperature: 0 °C
Yield: 89.4 %

Procedure:
To 20 ml of a pyridine solution containing 2.7 g of 2-cyclohexyloxyaniline was added dropwise 1.8 g of methanesulfonyl chloride under ice cooling with stirring. After completion of the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and made acidic with dilute hydrochloric acid. The crystals which formed were collected by filtration, washed with water and dried to give 3.8 g of the crude crystals, which were then recrystallized from ethanol-n hexane to give 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide.
Reaction SMILES: ClCC(O)=[O:4].[CH3:6][C:7]1[NH:12][C:11](=S)[NH:10][C:9](=[O:14])[C:8]=1[CH2:15][C:16]([OH:18])=[O:17]>>[CH3:6][C:7]1[NH:12][C:11](=[O:4])[NH:10][C:9](=[O:14])[C:8]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1CC(=O)O
Reactant: O=C(O)CCl
Product: Cc1[nH]c(=O)[nH]c(=O)c1CC(=O)O
Yield: 76.9 %

Procedure:
A 10% aq chloroacetic acid solution (150 mL; 159 mmol) was added to 2-(6-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetic acid (7.3 g; 36.5 mmol). The mixture was stirred under reflux for 24 h and cooled in an ice-bath. The formed solid was collected by filtration, washed with water and dried under reduced pressure to give 5.17 g (77%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:21][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:23][CH2:24][N:25]1[C:10](=[O:12])[CH2:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Product: COc1ccc(N2CCN(C(=O)Cc3c(F)cccc3F)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 33 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(2,6-difluorophenyl)acetic acid and (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine as starting materials. Product was obtained as an off-white solid (33%). LC/MS (Method B) 4.6 min, [M+1]+ 521.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:27]([C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=1[C:6]([C:5]1[CH:9]=[C:10]([CH2:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:8])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: CCc1cc(C(=O)O)cc(CC)c1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OC

Procedure:
The title compound was prepared according to the procedure in Example 1, step 4, using 3,5-diethyl-4-methoxybenzoic acid (10.66 g, 51.3 mmol), oxalyl chloride (4.90 mL, 56.3 mmol), N,N-DMF (2 drops), tin(IV) chloride (6.60 mL, 56.3 mmol) and 2-benzyl-4,5-dimethylfuran (11.4 g, 61.3 mmol) to give 22.0 g, of the title compound. 1H NMR δ1.13 (t, 6 H), 1.83 (s, 3 H), 2.19 (s, 3 H), 2.61 (q, 4 H), 3.74 (s, 3 H), 3.82 (s, 2 H), 7.05 (d, 2 H), 7.23-7.27 (m, 3 H), 7.42 (s, 2 H). mass spectrum (EI) m/z 376 (M+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:10]=[C:9]([NH:8][C:6]([C@H:2]5[CH2:3][CH2:4][CH2:5][NH:1]5)=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)[C@H]5CCCN5)c4)nc4ccccc34)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)[C@H]1CCCN1

Procedure:
To tert-butyl 5-(2-(3-((R)-pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (65 mg, 0.12 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ethyl ether to get a yellow solid. Product was purified using prep HPLC (method 25-50_70 mins) to afford (2R)—N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)pyrrolidine-2-carboxamide. (64 mg, 100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[C:19]=1[C:28]([O:30]C)=[O:29])(=[O:16])=[O:15])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[CH2:32]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[C:19]=1[C:28]([OH:30])=[O:29])(=[O:16])=[O:15])[CH3:33]
Reactant: CCN(CC)CC/C=C/c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCN(CC)CC/C=C/c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Yield: 70.4 %

Procedure:
A mixture of Example 529D (373 mg, 0.8 mmol) and LiI (428 mg, 4 equiv.) in 8 mL of pyridine was heated at 150° C. for 35 minutes in a microwave. The product was purified in two fractions by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 0% to 95% acetonitrile/0.1% aqueous TFA over 12 minutes (15 minute run time) at a flow rate of 70 mL/min to yield 257 mg (70%) of the desired product. MS (ESI(+)) m/e 457 (M+H)+; MS (ESI(−)) m/e 455 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 1.20 (t, J=7.27 Hz, 6H) 1.64 (m, 4H) 2.61 (m, 6H) 3.18 (m, 6H) 6.21 (ddd, J=15.40, 6.90, 6.79 Hz, 1H) 6.65 (m, 1H) 6.92 (d, J=8.23 Hz, 1H) 7.25 (d, J=15.64 Hz, 1H) 7.37 (t, J=8.23 Hz, 1H) 7.58 (t, J=7.96 Hz, 1H) 7.67 (m, 1H) 7.75 (dd, J=7.96, 1.37 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Sn](C)(C)C)[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](I)[CH:35]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F-].[Cs+]>[Cu]I.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.CN(C=O)C>[CH2:24]([O:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([C:18]2[CH:17]=[N:16][CH:15]=[C:14]([O:13][CH2:12][C@@H:9]3[CH2:10][CH2:11][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=2)[CH:37]=[CH:38][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([Sn](C)(C)C)c1
Reactant: Ic1cccc(CCOCc2ccccc2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(CCOCc3ccccc3)c2)c1
Temperature: 50 °C
Yield: 58.1 %

Procedure:
3-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)pyridine (619 mg, 1.45 mmol), 1-[2-(benzyloxy)ethyl]-3-iodobenzene (490 mg, 1.45 mmol), and anhydrous DMF (5.0 mL) were placed in a 25 mL round-bottom flask with magnetic stirrer. To this mixture were rapidly added CsF (441 mg, 2.90 mmol, 2.0 equiv.), CuI (27.5 mg, 0.14 mmol, 0.10 equiv.), and Pd(PPh3)4 (84 mg, 0.07 mmol, 0.05 equiv.). The flask was fitted with a three-way stopcock with nitrogen balloon, and the atmosphere was exchanged three times. The reaction mixture was heated at 50° C. for 5 h. TLC analysis of the crude reaction mixture indicated that the aryl iodide was absent. After evaporation of the solvent in vacuo, the residue was chromatographed on silica gel with EtOAc/petroleum ether/Et3N 2:4:0.05 to give the title compound (400 mg, 58%) as a colorless oil. LC-MS (ESI) m/z 475 (M+H+).