Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]2[NH:7][C:8](=[O:27])[C:9]([CH3:26])([CH3:25])[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[C:15]1[C:20]([O:21]C)=[CH:19][CH:18]=[CH:17][C:16]=1[O:23]C)=[O:4].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[C:14]1[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:25])([CH3:26])[C:8](=[O:27])[NH:7]3)[C:3](=[O:4])[O:21]2
Reactant: COC(=O)c1c(-c2c(OC)cccc2OC)ccc2c1NC(=O)C(C)(C)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC1(C)Nc2ccc3c(c2NC1=O)c(=O)oc1cccc(O)c13
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Quinoxalinone vii (420 mg, 1.14 mmol) was dissolved in dry CH2Cl2 (10 mL) and cooled to −78° C. under an atmosphere of N2. BBr3 (536 μL, 5.68 mmol) was added dropwise. After the addition, the reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was cooled to −78° C. and MeOH (3 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure and then diluted with water (30 mL) and extracted with EtOAc (7×50 mL). The organic layers were combined and solvent was removed under reduced pressure to provide crude product (350 mg) as a yellow solid. A small portion of the crude material was purified by reverse phase preparative HPLC for characterization, the rest of the crude was used directly for the next step without any further purification. 1H NMR (CD3OD) δ 8.74 (d, J=9 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 7.13 (t, J=9 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 1.33 (s, 6H). Anal. Calcd for C17H14N2O4 ⅙CF3COOH: C, 63.22; H, 4.34; N, 8.51. Found: C, 63.54; H, 4.50; N, 8.32.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([N:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)=[O:19])=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(C2=CCNCC2)nc1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(C2=CCN(C(=O)c3ccccc3)CC2)nc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, J=2.5 Hz, 1H), 8.61 (s, 1H), 8.01 (dd, J=8.6, 2.2 Hz, 1H), 7.42-7.54 (m, 6H), 7.35-7.39 (m, 2H), 7.29-7.35 (m, 2H), 6.46-6.67 (m, 1H), 4.79 (s, 4H), 4.05-4.32 (m, 2H), 3.77-3.94 (m, 1H), 3.47-3.58 (m, 1H), 2.61-2.65 (m, 2H); MS (ESI(+)) m/e 425 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]=1[NH2:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:34]([O:36][CH2:37][C:38](Cl)=[O:39])[CH3:35]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]=1[NH:26][C:38](=[O:39])[CH2:37][O:36][CH2:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC(=O)Cl
Reactant: Cc1cc(NCCOCc2ccccc2)c(N)c(Oc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(NCCOCc2ccccc2)cc(C)nc1Oc1ccccc1
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
Under a nitrogen atmosphere, a solution of N4-[2-(benzyloxy)ethyl]-6-methyl-2-phenoxypyridine-3,4-diamine (3.80 g, 10.9 mmol), anhydrous dichloromethane (75 mL), and anhydrous triethylamine (1.8 mL, 13 mmol) was cooled to 5° C. Ethoxyacetyl chloride (1.40 g, 11.4 mmol) was then added over a period of 30 seconds, and the reaction was stirred for 20 minutes. The reaction mixture was washed with aqueous sodium bicarbonate (3×), and the combined aqueous washings were extracted with chloroform (3×). The combined organic solutions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a white powder. The powder was dried for three days under vacuum at room temperature to provide 4.01 g of N-{4-[2-(benzyloxy)ethylamino]-6-methyl-2-phenoxypyridin-3-yl}-2-ethoxyacetamide as a white solid.
Reaction SMILES: I[CH2:2][C:3](=[CH2:13])[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:9]([Si:6]([CH3:8])([CH3:7])[O:5][CH2:4][C:3]([CH2:2][O:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:18][CH:19]=1)=[CH2:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: C=C(CI)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(COc1ccc(OC(F)(F)F)cc1)CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 11 h
Yield: 58.2 %

Procedure:
A mixture of iodide 165 (4.63 g, 14.8 mmol), 4-(trifluoromethoxy)phenol (3.10 mL, 23.9 mmol) and powdered K2CO3 (3.56 g, 25.8 mmol) in acetone (10 mL) was stirred at 50° C. for 11 h. The resulting cooled mixture was diluted with ice-water (100 mL) and extracted with CH2Cl2 (4×100 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-3% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 5-10% CH2Cl2/petroleum ether gave tert-butyl(dimethyl)[(2-{[4-(trifluoromethoxy)phenoxy]methyl}-2-propenyl)oxy]silane (166) (3.12 g, 58%) as a colourless oil; 1H NMR (CDCl3) δ 7.12 (br d, J=9.0 Hz, 2H), 6.90 (dt, J=9.1, 2.9 Hz, 2H), 5.27 (d, J=0.7 Hz, 1H), 5.20 (d, J=1.1 Hz, 1H), 4.54 (s, 2H), 4.24 (s, 2H), 0.91 (s, 9H), 0.07 (s, 6H); HRFABMS calcd for C17H26F3O3Si m/z [M+H]+ 363.1603. found 363.1604.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1CCC(OC)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 20. (+3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.047 mmol) and triethylamine (13.1 μL, 0.0938 mmol) in tetrahydrofuran (3 ml), was added iodoethane (5.6 μL, 0.070 mmol). Analysis show 60% conversion. MS m/z (relative intensity, 70 eV) 241 (M+, 9), 226 (74), 211 (28), 141 (47), 71 (bp).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=4)[N:17]=[CH:16][N:15]=3)[C:6]=2[CH:12]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Brc1ccc2c(c1)NCCCC2
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCCCc4ccc(Br)cc43)c2cc1OC
Yield: 58 %

Procedure:
Utilizing a procedure analogous to that described in Example 47, this product was prepared in 58% yield from 8-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (M.P. 209°-217° C.; LC-MS: 414, 416 (MH+); anal. RP18-HPLC RT: 5.47 min.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:6]([N:8]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]([CH3:28])([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22])=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[C:12]([C:29]([CH3:36])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])[CH:13]=3)[CH:7]=1.[Li]CCCC.C([O:52][B:53](OC(C)C)[O:54]C(C)C)(C)C>C1COCC1.CCCCCC>[CH3:28][C:21]([C:17]1[CH:18]=[CH:19][C:20]2[N:8]([C:6]3[C:5]([O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)=[C:4]([B:53]([OH:54])[OH:52])[CH:3]=[C:2]([CH3:1])[CH:7]=3)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([C:29]([CH3:30])([CH2:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:36])=[CH:11][CH:10]=3)([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH3:22]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(OC2CCCCO2)c(-n2c3ccc(C(C)(C)CC(C)(C)C)cc3c3cc(C(C)(C)CC(C)(C)C)ccc32)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(B(O)O)c(OC2CCCCO2)c(-n2c3ccc(C(C)(C)CC(C)(C)C)cc3c3cc(C(C)(C)CC(C)(C)C)ccc32)c1
Reaction time: 3 h
Yield: 78.1 %

Procedure:
The 9-(5-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-3,6-bis(2,4,4-trimethylpentan-2-yl)-9H-carbazole (5.00 g, 8.6 mmol) is dissolved in 50 mL THF in a 250 mL round bottom flask in an ice water bath. n-BuLi (7.0 ml of a 1.6 M solution in hexane, 11.2 mmol) is added dropwise via syringe (soln turns yellow in color) and the brown solution stirred for 3 hours. Triisopropylborate (2.37 mL, 11.2 mmol) is added dropwise via syringe and the solution stirred for one hour, during which time the mixture became turbid and darkened in color. The mixture is quenched with 100 mL ice water. The solution is extracted with 2×100 mL Et2O. The combined organic portions are dried with MgSO4, filtered and rotovapped down to a white solid (5.1 g). This solid is added to 200 mL water and stirred for 1.5 hrs. The mixture is extracted with 150 and 100 mL Et2O. The combined organic extract is dried with MgSO4, filtered and rotovapped down to yield 4.2 g (78% yield) of a white powder. 1H NMR (CDCl3): δ 8.07 (d, JH—H=1.4 Hz, 1H, CBZ), 8.04 (d, JH—H=1.4 Hz, 1H, CBZ), 7.69 (d, JH—H=2.3 Hz, 1H, aryl), 7.42 (dd, JH—H=8.6, 1.8 Hz, 2H, CBZ), 7.40 (dd, JH—H=8.6, 1.7 Hz, 1H, CBZ), 7.37 (d, JH—H=2.3 Hz, 1H, aryl), 7.18 (d, JH—H=8.6 Hz, 1H, CBZ), 6.99 (d, JH—H=8.6 Hz, 1H, CBZ), 6.34 (s, 2H, OH), 3.80 (m, 2H, THP), 2.91 (m, 1H, THP), 2.39 (s, 3H, aryl Me), 1.89 (dd, JH—H=12.8, 4.2 Hz, 2H, tOCT CH2), 1.82 (d, JH—H=14.5 Hz, 2H, tOCT CH2), 1.55 (s, 3H, tOCT CMe2), 1.52 (s, 3H, tOCT CMe2), 1.48 (s, 3H, tOCT CMe2), 1.45 (s, 3H, tOCT CMe2), 0.71 (s, 9H, tOCT tBu), 0.70 (s, 9H, tOCT tBu).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:28])[CH2:12][O:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=2)=[N:9]1.O>O1CCCC1>[CH3:7][C:8]1([CH3:28])[CH2:12][O:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)=[N:9]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(C(=O)O)cc2)=N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reaction time: 2 h
Yield: 88.3 %

Procedure:
1.28 g (33.7 mmol) of aluminum lithium hydride was suspended in tetrahydrofuran (20 ml). At room temperature, 5.0 g (16.9 mmol) of 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline was gradually added thereto, followed by stirring for 2 hours. After the reaction liquid was cooled with ice, 100 ml of water was added thereto to conduct hydrolysis, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 4.2 g of the title compound (yield 88%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].CS[C:17](=[NH:19])[NH2:18].O.[OH-].[Na+]>C(O)C>[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSC(=N)N
Reactant: NCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N=C(N)NCCc1ccccc1
Yield: 127 %

Procedure:
2-Phenylethylamine (8.49 g, 70.1 mmol) and S-methylisothiourea sulfate (9.43 g, 33.9 mmol) was dissolved in 100 ml destilled water. Air was passed over the reaction mixture and through 50% NaOH (500 ml) and then through 5% cuprous sulfate (250 ml). The reaction mixture was heated at reflux for 5 hours. Evaporation of the solvent yielded a white powder. The product was isolated by crystallisation from 96% ethanol, washed with cold acetone and diethyl ether and dried in a desicator. After three crystallisations, the product contained only minor amounts of starting material. The reaction yielded 61.5% (9.14 g) 2-phenylethylguanidine hemisulfate.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[NH:14][CH2:13][CH2:12][CH:11]2[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26].[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH2:18][CH:11]1[C:10]2[C:15](=[N:16][CH:17]=[C:8]([C:37]3[CH:36]=[N:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)[CH:9]=2)[NH:14][CH2:13][CH2:12]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1ccc(F)c(CC2CCNc3ncc(Br)cc32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(Cc3cc(F)ccc3F)CCN4)cn2)CC1
Yield: 26 %

Procedure:
Na2CO3 (2N, 53 μL) (4.0 eq) was added to a mixture of 6-bromo-4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (9.0 mg) (1 eq), 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (11.3 mg) (1.4 eq), and Pd(PPh3)4 (3.0 mg, 0.1 eq) in toluene/ethanol (4:1, v/v, 2 mL). The reaction was heated at 90° C. for six (6) hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (15 mL) and washed with water (15 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-20% methanol/CH2Cl2 as the eluting solvent to give the title compound as a yellow foam (26% yield). LCMS: m/z=436 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.7-2.0 (m, 2H), 2.37 (s, 3H), 2.55-2.60 (m, 4H), 2.81 (dd, J=9.1 and 13.3 Hz, 1H), 2.98 (dd, J=6.4 and 13.3H, 1H), 3.08-3.18 (m, 1H), 3.40-3.50 (m, 1H), 3.53-3.70 (m, 5H), 5.18 (bs, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.81-6.87 (m, 1H), 6.89-6.96 (m, 1H), 6.98-7.06 (m, 1H), 7.16 (d, J=1 Hz, 1H), 7.50 (dd, J=2.5 and 8.8 Hz, 1H), 8.05 (d, J=1 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:20].O>C(OCC)C>[Br:20][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OC(c1ccccc1)c1cccc2ccccc12
Solvent: CCOCC
Solvent: O
Product: BrC(c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.5 %

Procedure:
To a solution of 32.3 g (138 mmol) of 7 in 150 mL of dry diethyl ether, 24.8 g (8.62 mL, 91.6 mmol) of PBr3 was added at −10° C. The resulting mixture was stirred for 12 hr at room temperature and then added to 450 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 2×150 mL of water. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, and then evaporated to dryness. This procedure gave 37.7 g (92%) of 8.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:43][C:44](=[O:46])[CH3:45].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH2:43][C:44](=[O:46])[CH3:45])[CH2:32][CH2:31]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CC(=O)CCl
Reactant: Nc1ncnn2c(CCCN3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CN1CCN(CCCc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 50 °C
Yield: 12.9 %

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-(3-piperazin-1-yl-propyl)pyrrolo-[2,1-f][1,2,4]triazin-4-ylamine (75 mg, 0.16 mmol) was dissolved in anhydrous DMF (3.2 mL) and treated with K2CO3 (33 mg, 0.24 mmol) followed by the addition of chloroacetone (15 μL, 0.19 mmol). The mixture was heated to 50° C. for 18 h, cooled to rt and poured into water. The aqueous layer was extracted with 3×10 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (10.8 mg, 13%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.87 (s, 1H), 7.79 (d, 1H), 7.57 (s, 1H), 7.36 to 7.29 (m, 5H), 7.13 (d, 1H), 6.59 (s, 1H), 5.64 (s, 2H), 3.27 to 3.24 (m, 1H), 3.09 (s, 2H), 2.87 (t, 2H), 2.36 to 2.23 (m, 9H), 2.04 (s, 3H), 1.88 to 1.79 (m, 2H); ES-MS m/z 523.2 [M+H]+, RT (min) 2.08.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:18]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[S:13][C:14]([Cl:18])=[C:15]([CH3:17])[N:16]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2nc(C)cs2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(Cl)s2)CC1

Procedure:
A solution of cis/trans-4-(4-methyl-thiazol-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:5) (200 mg, 0.789 mmol) and N-chlorosuccinimide (116 mg, 0.868 mmol) in N,N-dimethylformamide (1.6 ml) was stirred for 1 h at 50° C. The reaction mixture was partitioned between tert-butyl methyl ether (25 ml) and 0.1 M aqueous sodium hydroxide solution (25 ml). The layers were separated. The aqueous layer was extracted with one 25-ml portion of tert-butyl methyl ether. The combined organic layers were washed with three 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (209 mg, 92%) as light yellow solid, which was used in the next step without further purification. MS m/e: 288 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:5]=1[N:6]([CH2:10][CH2:11][CH3:12])[CH2:7][CH2:8][CH3:9])[CH3:2].P(Cl)(Cl)(Cl)=O.CN(C)[CH:27]=[O:28]>>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH:27]=[O:28])[C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:5]=1[N:6]([CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)c1cc(OCC)ccc1OCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)c1cc(OCC)c(C=O)cc1OCC
Temperature: 0 °C

Procedure:
2,5-Diethoxy-4-formyl-N,N-di-n-propylaniline was prepared in situ by taking 2,5-diethoxy-N,N-di-n-propylaniline (2.65 g., 0.01 mole) in a mixture of N,N-dimethylformamide (10 ml.) and phosphorus oxychloride (1.68 g., 0.011 mole) and heating on a steam bath for two hours. The mixture was then poured into ice water to give the coupling solution.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[CH2:5][C:6]([F:15])([F:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.O.O>[F:15][C:6]([F:14])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][C@H:4]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)=[O:18])[C:3]([OH:25])=[O:2]
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Solvent: O
Solvent: CO
Product: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a solution of (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid methyl ester (2.81 g, 7.88 mmol) in MeOH:H2O (2:1 vol, 40 mL) is added LiOH mono hydrate (662 mg, 15.76 mmol). The mixture is stirred at room temperature for 2.5 h, and then diluted with water (30 mL). Methanol is removed in vacuum. The pH is adjusted to pH 1 with 6N HCl and the aqueous layer is extracted with dichloromethane (2×30 mL). The organic layers are dried over magnesium sulfate and concentrated in vacuum to afford (S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid (2.509 g, 93%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[S:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:9]1)C1C=CC=CC=1.Cl>C1COCC1.CO.[Pd]>[C:27]1([S:24]([C:18]2[C:17]3[C:21](=[CH:22][CH:23]=[C:15]([O:14][CH:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[CH:16]=3)[NH:20][N:19]=2)(=[O:25])=[O:26])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCCN(Cc4ccccc4)C3)cc12
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCCNC3)cc12
Reaction time: 72 h

Procedure:
A mixture of 5-(1-benzylpiperidin-3-yloxy)-3-(1-naphthylsulfonyl)-1H-indazole (0.7 g, 1.4 mmoles), 10% Pd/C and concentrated HCl (1 mL) in THF and methanol was hydrogenated in a Parr hydrogenation bottle at 52 lb/in2 for 72 hours. TLC showed about 30% conversion into desired product. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The concentrate, a mixture of starting material and product, was then separated by reverse phase chromatography on C18 column, using as eluent 10-100% H2O/AcCN, to afford the title compound as an off-white solid, 0.16 g, mp 178-180° C., identified by HNMR and mass spectral analyses, MS (ES) m/z 406.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][N:21]([CH3:32])[C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:36])[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][N:21]([CH3:32])[C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(CCCN(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)cn1)C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCCN(C)C(=O)c1ccc(N(C)C(=O)OC(C)(C)C)cn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
The compound (170 mg, 0.372 mmol) obtained in Example 6a was dissolved in tetrahydrofuran (4 mL), sodium hydride (55%; 20 mg, 0.447 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. Methyl iodide (35 μL, 0.558 mmol) was added, and then the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate (×3), and the organic layer was washed with saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (178 mg; yield, 100%) as a yellow oily substance.