Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(NC(C)C)(C)C.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:34](=[O:37])[CH2:35][CH3:36])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(OC)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.4 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (4 mL) were added N,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) and propionyl chloride (69 mg, 0.75 mmol) and the reaction mixture was stirred at ambient temperature for 22 h. After heating at 50° C. for another 26 h the resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and concentration afforded the title compound (206 mg, 89%) as a yellow solid. MS: m/e=405.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=3)[CH:9]=2)[CH:4]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2)c1

Procedure:
The title compound was prepared by reacting 6-methoxy-2-bromonaphthalene (3.99 g, 13.0 mmol) with 3-methoxyphenylboronic acid (2.18 g, 14.3 mmol according to method A to yield 1.18 g (34%) of a white solid: mp 80° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 3.92(3H, s), 6.90 (1H, dd, J=2.17 Hz, J=7.76 Hz), 7.14–7.18 (2H, m), 7.22–7.24 (1H, m), 7.28 (1H, d, J=7.45 Hz), 7.36–7.39, (1H, m), 7.70 (1H, dd, J=1.86 Hz, J=8.70 Hz), 7.77–7.80 (2H, m), 7.96 (1H, d, J=1.24 Hz); MS (ESI) m/z 265 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[N:27]1.N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:31]([C:29]2[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=2)(=[O:33])=[O:32])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:5][N:4]=1
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(=O)(=O)c1cnn(C)c1
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 111 mg (0.61 mmol) 1-methyl-1H-pyrazole-4-sulfonyl chloride and 72 μL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 101 mg (70%). HPLC-MS: M+H=470; tR=0.72 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[N:7]=1.C(N(C(C)C)[CH:17]([CH3:19])[CH3:18])C.C(I)(C)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([O:13][CH:17]([CH3:19])[CH3:18])=[O:12])[N:10]=2)[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1nc2ccc(Cl)nn2n1
Solvent: CN(C)C=O
Solvent: CC(C)I
Solvent: O
Product: CC(C)OC(=O)c1nc2ccc(Cl)nn2n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2.14 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 5.57 ml of N-ethyldiisopropylamine were dissolved in 30 ml of N,N-dimethylformamide; 3.23 ml of isopropyl iodide was added, followed by stirring at room temperature for 10 hours and at 50° C. for 3 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 2.21 g of the title compound.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]#[N:12].[C:13](OCC)(=[O:15])[CH3:14]>>[C:11]([CH:10]([C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[CH3:2])[C:13](=[O:15])[CH3:14])#[N:12]
Reactant: Cc1ccc(CC#N)c(C)c1
Reactant: CCOC(C)=O
Agent: [Na]
Product: CC(=O)C(C#N)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Sodium pellets (9.8 g, 0.43 mol) were added portionwise to a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 mL) at ambient temperature. The reaction mixture was heated to reflux temperature and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with copious amounts of ether and then air-dried. The solid was dissolved in water and a 1N HCl solution was added until the pH=5-6. The mixture was extracted with ethyl acetate (3×200 mL); the combined organic layers were dried over MgSO4 and filtered. Solvent was removed in vacuo to afford a white solid (45.7 g, 74% yield): NMR (CDCl3, 300 MHz):; CI-MS: 188 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.O1CCCC1.O.C(=O)([O-])[O-].[Na+].[Na+].[I:24]I>>[OH:10][C:8]1[C:7]([I:24])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)c1cncc(O)c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(I)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To solution of 5-hydroxy-nicotinic acid methyl ester (2.50 g, 16.3 mmol) in tetrahydrofuran (50.0 mL, 616 mmol)/water (50.0 mL, 2780 mmol) was added sodium carbonate (5.19 g, 49.0 mmol) and iodine (10.4 g, 40.8 mmol). The reaction mixture was stirred at room temperature 4h. The aqueous layer containing product was separated and wash with hexane. The organic layer was neutralized to pH 7 with HCl, extracted EtOAc 4×. The combined organic layers was dried Na2SO4, concentrated. The crude product was purified by flash chromatography (EtOAc/DCM) (eluted at 40 EtOAc) to give methyl 5-hydroxy-6-iodonicotinate (81.2%) MS: (ESI+) 280.0
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])[CH2:35][CH2:34]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 78 %

Procedure:
Phenyl N-(2-methoxyquinoline-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:11][C:10]=1[C:21]([O:23]C)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Temperature: 65 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-(4-chlorophenyl)thiophene-2-carboxylate a (0.135 g, 0.29 mmol) in 1:1 THF/MeOH (2 mL) at rt was added a 3 N aq NaOH (1 mL) and the resulting mixture was warmed to 65° C. for 30 min then cooled to rt and concentrated to remove the volatile solvents. The remaining aqueous portion was cooled in an ice bath and 1 N aq HCl was added until pH˜2 was reached. The slurry was stirred for 1 h then collected the resulting solid by vacuum filtration, rinsed with water and dried under vacuum to afford 86 mg (66%) of an off-white solid as compound b. HPLC Ret time=4.32 min.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C=O.[C:18]([BH3-])#N.[Li+].C(O)(=O)C>C(#N)C.C(OCC)C>[CH3:18][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3]1
Reactant: [BH3-]C#N
Reactant: CCOC(=O)C1C=Nc2ccccc2O1
Agent: C=O
Agent: [Li+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C1=CN(C)c2ccccc2O1
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
Ethyl 1,4-benzoxazine-2-carboxylate (5.8g.) was dissolved in acetonitrile (15ml.) under an atmosphere of argon. Formaldehyde (30ml. of a 37% aqueous solution) and lithium cyanoborohydride (4.67g.) were added, and the solution was stirred for 5 minutes. Glacial acetic acid (3.5ml.) was added dropwise and over a period of 10 minutes, and the solution was stirred at room temperature for 2 hours. More glacial acetic acid (3.5ml.) was added, and after 30 minutes the reaction mixture was poured into diethyl ether (200ml.), washed successively with 0.1N hydrochloric acid, sodium bicarbonate and brine, and was dried. The solvent was evaporated to give the crude 2-carboxyethyl-4-methyl-1,4-benzoxazine, which was purified by chromatography on silica gel (148g.). Elution with 10% ethyl acetate in toluene gave pure ethyl 4-methyl-1,4-benzoxazine-2-carboxylate (5.9g.) whose n.m.r. spectrum in deuteriochloroform showed the following features (δ values):
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C3C=CC=CC=3)[C@@H:13]([O:14]C(=O)C)[C@@H:12]2[F:30])=[C:4]([NH2:31])[N:3]=1.CC#N.O.O.[OH-].[Li+]>C(O)(=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@@H:12]2[F:30])=[C:4]([NH2:31])[N:3]=1
Reactant: CC(=O)O[C@H]1[C@H](F)[C@H](n2cnc3c(N)nc(F)nc32)O[C@@H]1COC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 1f (430 mg, 0.99 mmol) in 1:1 MeCN-H2O (40 mL) was treated in one portion with solid lithium hydroxide monohydrate (125 mg, 2.97 mmol). The reaction became a clear solution after being stirred at room temperature for 20 minutes. A 3-h TLC aliquot showed the deblocking to be Glacial acetic acid (57 μl) was added, and the solution was evaporated until white solid deposited. After being chilled, the solid was collected, washed with cold water, and dried in vacuo at room temperature to give crude 1g, 252 mg. This solid was dissolved in 40 mL of water and applied to a water-equilibrated SM-4 Bio-Bead column (1.5×32 cm). After initial elution with water, the product was eluted with a stepwise gradient, 5% →20% EtOH in water. The residue from the combined, evaporated column fractions was crystallized from 25 mL of boiling water with charcoal treatment and dried in vacuo at 56° C. for 16 hours to give pure 1g: 178 mg (59%). Mp 207°-209° C.; TLC 5:1 CHCl3 -MeOH, Rf 0.50; HPLC 99%, 9:1 H2O-MeCN; MS, z/e 288 (M+1)+ ; UV λ max pH 1 261 (14.0), 268 (sh), pH 7 260 (15.1), 268 (sh), pH 13 261 (14.9), 268 (sh). Anal. Calcd. for C10H11F2N5O3 ·H2O: C, 39.35; H, 4.29; N, 22.94. Found: C, 39.51; H, 4.21; N, 22.94.
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:4]1([C:7](OCC)=[O:8])[CH2:6][CH2:5]1)#[N:2].N.[H][H]>[Ni]>[C:15]1([C@@H:13]([NH:12][C@H:3]2[C:4]3([CH2:6][CH2:5]3)[C:7](=[O:8])[NH:2][CH2:1]2)[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1([C@@H](C#N)N[C@@H](C)c2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: C[C@H](N[C@@H]1CNC(=O)C12CC2)c1ccccc1
Temperature: 180 °C
Yield: 73.4 %

Procedure:
An autoclave was charged with 1.0 g of 1-[(S)-1-cyano-[(S)-1-phenylethylamino]methyl]-1-ethoxycarbonylcyclopropane, 1.7 ml of Raney nickel and 17 ml of ammonia-saturated ethanol, and the contents were stirred at room temperature for 1.5 hours in an atmosphere of hydrogen under a pressure of 35 kg/cm2. After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. The resulting residue was dissolved in 20 ml of ethanol, put into an autoclave and heated at 180° C. for 8.5 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure, and the resulting residue was mixed with isopropanol and stirred to obtain 621 mg (74%) of the title compound in the form of slightly yellow crystals. The thus obtained compound was recrystallized from ethanol and isopropanol, and used as a sample for analyses.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([C:20]3[C:25]([F:26])=[CH:24][N:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:21]=3)[CH3:19])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.O.[OH-].[Li+]>CO.C1COCC1>[F:26][C:25]1[C:20]([N:18]([CH3:19])[CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:6]=[CH:7]3)=[N:21][C:22]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:23][CH:24]=1
Reactant: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(-c4ccc(OC)cc4)ncc3F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ncc(F)c(N(C)CCCOc3ccc4c(ccn4CC(=O)O)c3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of methyl(5-{3-[[5-fluoro-2-(4-methoxyphenyl)-4-pyrimidinyl](methyl)amino]propoxy}-1H-indol-1-yl)acetate (Example 86, 0.1 g, 0.20 mmol) in methanol (2 mL), THF (2.00 mL), and water (1.00 mL) was added lithium hydroxide (0.05 g, 1.99 mmol). The mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was taken up in water and washed with ether. The aqueous layer was acidified to pH 3.5 and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give the title compound (0.092 g, 100%). 1H NMR (300 MHz, CD3OD) δ 8.20-8.17 (m, 2H), 8.03-8.01 (m, 1H), 7.18-6.78 (m, 6H), 6.33-6.30 (m, 1H), 4.74 (s, 2H), 4.11 (t, 2H), 3.94 (t, 2H), 3.83 (s, 3H), 3.36-3.34 (m, 3H), 2.26-2.20 (m, 2H). LC/MS m/z 465.2 (M+H)+, RT 2.51 min.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCCC(=O)O)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A 500 ml single-neck flask was charged with 7-(4-methoxyphenyl)heptanoic acid (A3) (20.0 g, 90 mmole), freshly distilled 48% hydrobromic acid (80 ml), and glacial acetic acid (40 ml). The mixture was heated to reflux by immersing the flask in an oil bath regulated at 140° C. for 3.5 hours. At the end of this time, water (80 ml) was added, the flask was cooled to room temperature, and placed in the refrigerator overnight. The resulting solid, 7-(4-hydroxyphenyl)heptanoic acid, was collected by suction filtration, washed with water (2×80 ml), and dried in vacuo. The product was of sufficient purity to be used in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([O:12][CH2:24][CH2:23][CH2:22][C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: OCCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCCCc1cccnc1
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (3.0 g; 13.9 mmol), 3-(3-Pyridyl)-1-propanol (2.90 g; 20.9 mmol), dicyclohexylcarbodiimide (4.59 g; 22.24 mmol), camphorsulfonic acid (1.08 g; 4.63 mmol), and 4-dimethylaminopyridine (0.60 g; 4.63 mmol) in dry methylene chloride (100 mL) was stirred overnight. The reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water (3×100 mL), dried over magnesium sulfate, and concentrated, and the crude residue was purified on a silica gel column eluting with ethyl acetate to obtain 4.60 g (95%) of the ester as a thick oil. 1H NMR (300 MHz, CDCl3): δ 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1H); 2.71 (t, 2H); 3.50 (m, 2H); 4.15 (m, 2H); 4.18 (m, 1H); 7.24 (m, 1H); 7.51 (m, 1H); 8.48 (m, 2H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](Br)=[CH:17][CH:16]=1.N[CH:27](N)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[C:15]1([C:27]2[CH:32]=[CH:31][C:30]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[NH:12][C:13]3[CH:1]=[CH:2][C:3]([C:1]5[CH:13]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:4][C:5]4=3)=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCCCCC(N)N
Reactant: Brc1ccc(Br)c2ccccc12
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(-c2ccc3[nH]c4ccc(-c5ccc(-c6cccc7ccccc67)cc5)cc4c3c2)cc1
Yield: 6 %

Procedure:
As depicted in Reaction 6, a solution of 10 g (31.3 mmol) of carbazole, 13.5 g (31.3 mmol) of 1,4-dibromonaphthalene, CuI, diaminohexane and K3PO4 in dioxane was refluxed for 15 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. After the solvent was removed under reduced pressure, the residue was purified by column chromatography to give the title compound. The product was collected by filtration under reduced pressure and dried. Yield: 6%. MS (EI) (Calcd. for C34H22BrN: 523.09. Found: 523).
Reaction SMILES: [N:1]1([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH:23]([CH2:33][CH3:34])[C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25].C(N(CC)C(C)C)(C)C>CC(O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:33][CH2:34][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:21]=[C:10]4[N:11]=[CH:12][CH:13]=[C:14]([C:15]5[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=5)[N:9]4[N:8]=3)[CH2:6][CH2:5]2)=[CH:31][CH:30]=1
Reactant: CCC(Cl)C(=O)c1ccc(F)cc1
Reactant: c1cc(-c2ccnc3nc(N4CCNCC4)nn23)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(CCCN1CCN(c2nc3nccc(-c4ccncc4)n3n2)CC1)c1ccc(F)cc1
Yield: 13.5 %

Procedure:
A mixture of 5.6 g (0.02 moles) of 2-(1-piperazinyl)-7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described in Example 47), 4.0 g (0.02 moles) of α-chloro-p-fluorobutyrophenone, 3.6 g (0.027 moles) of N,N-diisopropylethylamine and 100 ml of 2-propanol was heated at reflux for 16 hours with stirring. The reaction mixture was evaporated in vacuo to a solid. The solid was dissolved in 100 ml of water and extracted twice with 100 ml of chloroform. The extracts were combined, dried over magnesium sulfate, filtered and evaporated to a dark syrup. The syrup was dissolved in dichloromethane and passed through a pad of magnesium silicate, washing with methylene chloride. This filtrate was collected and set aside. Then acetone was passed through the pad and the acetone filtrate was collected and evaporated to a syrup. The syrup was dissolved in 15 ml of ethanol, 200 ml of ether was added, then hexane until cloudy. Evaporation by boiling caused crystallization. The crude product was collected and washed with ether. Recrystallization from ethanol gave 1.2 g of the desired product as yellow crystals, mp 133°-135° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]4)[CH:27]=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:3][CH2:2]1.I[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][N:43]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[NH:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:8]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:32][CH2:33][CH:34]([C:37]([OH:40])([CH3:38])[CH3:39])[CH2:35][CH2:36]4)[CH:27]=[CH:26][C:9]=3[N:10]=2)=[N:43]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1
Reactant: Ic1n[nH]c2ccccc12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4n[nH]c5ccccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
To a degassed solution of 2-(1-((4-morpholino-2-(tributylstannyl)pyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 136 (0.15 g) and 3-iodo-1H-indazole (1.4 eq) in 1,4-dioxane (1.4 mL) was added Copper(I) thiophene-2-carboxylate (1 eq) and Tetrakis(triphenylphosphine)palladium(0) (0.125 eq). The reaction was microwaved at 140° C. for 30 minutes and then loaded onto biotage isolute scx-2 catridge and eluted with 2M ammonia in Methanol. The crude material was purified by reverse phase HPLC to afford 23.4 mg of 138. MS (Q1) 488.3 (M)+