Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH2:32]([N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH2:44]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:44][C:40]2[N:39]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:43]=[CH:42][N:41]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: ClCc1nccn1Cc1ccccc1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3nccn3Cc3ccccc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 1-benzyl-1H-imidazol-2-ylmethyl chloride. The crude product is purified by column chromatography eluting with 2% MeOH/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:65])([CH3:64])[C@H:42]([N:50]1[CH2:54][CH2:53][N:52]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH3:62])[N:57]=2)[C:51]1=[O:63])[C:43](OC(C)(C)C)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:65])([CH3:64])[C@H:42]([N:50]1[CH2:54][CH2:53][N:52]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH3:62])[N:57]=2)[C:51]1=[O:63])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A solution containing the product from Example 2C (1.0 g, 1.88 mmol) in THF (19 mL) was treated with the product from Example 10B (0.83 g, 1.98 mmol), DEPBT (0.84 g, 2.8 mmol), and N,N-diisopropylethylamine (1.6 mL, 9.2 mmol), stirred at 25° C. for 16 hours, and partitioned between a mixture of dichloromethane and ethyl acetate (2:1, respectively) and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (1.15 g, 75% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.90 (s, 9 H), 1.55 (m, 2 H), 2.38 (q, J=9.44 Hz, 1 H), 2.46 (s, 3 H), 2.57 (m, 1 H), 2.67 (d, J=7.35 Hz, 2 H), 2.79 (m, 1 H), 2.97 (m, 1 H), 3.09 (q, J=8.95 Hz, 1 H), 3.21 (m, 1 H), 3.50 (s, 3 H), 3.67 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.12 (m, 3 H), 4.35 (m, 2 H), 4.54 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.56 Hz, 1 H), 7.09 (m, 7 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.49 (d, J=9.56 Hz, 1 H), 7.69 (t, J=7.54 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [C:1]([N:4]1[CH2:7][C:6]2([CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:13]=3)[O:8]2)[CH2:5]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1>C(Cl)Cl>[C:1]([N:4]1[CH2:7][C:6]2([CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12](/[CH:18]=[CH:19]/[C:20]([NH:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)=[O:21])[CH:13]=3)[O:8]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 30 %

Procedure:
A suspension of (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (100 mg, 0.30 mmol) in DCM (3 ml) was treated with TEA (0.060 ml, 0.49 mmol) and then with EDC (94 mg, 0.49 mmol), HOBt (67 mg, 0.49 mmol) and NH2OTHP (50 mg, 0.43 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (36 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11].C(C1C=CC=CN=1)(=O)C.[NH2:25][C:26]1[C:30]([C:31]#[N:32])=[CH:29][NH:28][N:27]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]2[N:28]=[CH:29][C:30]([C:31]#[N:32])=[C:26]2[N:25]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Reactant: N#Cc1c[nH]nc1N
Agent: CC(=O)c1ccccn1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccccn3)nc12
Yield: 46.7 %

Procedure:
Reaction of 1-pyridin-2-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 2-acetylpyridine according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light brown solid (135 mg, 47%). MS (ISP) 289.9 [(M+H)+]; mp 208° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:31]([C:34]1[CH:35]=[C:36]([NH:40][C:41](=[O:49])OC2C=CC=CC=2)[CH:37]=[CH:38][CH:39]=1)(=[O:33])[NH2:32]>>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:36]4[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=4)[C:31]([NH2:32])=[O:33])=[O:49])=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: NC(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4cccc(C(N)=O)c4)cc3)nc(N3CCOCC3)n2)cc1
Yield: 4 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 51 mg, 4% yield.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[NH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH:12][N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(=O)CC1
Reactant: Nn1cccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCN1CCC(Nn2cccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A solution of 1-butyl-4-piperidone (6.2 g, 40 mmole) and 1-aminopyrrole (3.3 g, 40 mmole) in 100 ml of toluene was stirred at reflux overnight (about 16 hours). The mixture was cooled and then evaporated to an oil, which in turn was dissolved in 75 ml of isopropanol, and 22 ml of ethanol. To the solution was added NaBH4 (3.8 g, 100 mole). The mixture was stirred at 70° C. for 2 hours and then evaporated, stirred with water and extracted with ethyl acetate-ether. The organic extract was washed with water and saturated NaCl solution, dried (anhydrous MgSO4), filtered and evaporated to 13 g of an oil. This oil was purified by high pressure liquid chromatography (silica, 1% diethylamine/ethyl acetate) to give 8.2 g of an oil of 1-(n-butyl)-4-(1H-pyrrol-1-yl)aminopiperidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:8][N:7]=1)=O)C.O.[NH2:21][NH2:22]>C(O)C>[Si:13]([O:12][CH2:11][C:9]1[O:8][N:7]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[CH:10]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: NN
Reactant: CCOC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)on1
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(=O)NN)no1
Temperature: 60 °C

Procedure:
A mixture of ethyl-5-({[tert-butyl(dimethylsilyl)]oxy}methyl)isoxazole-3-carboxylate (1.68 g, 5.9 mmol) and hydrazine hydrate (44 g, 8.8 mmol) in ethanol (30 mL) is heated to 60° C. for 4 hours. The mixture is cooled to room temperature and the solvents are removed in vacuo to yield 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)isoxazole-3-carbohydrazide as orange crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:45]=[CH:44][CH:43]=[CH:42][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH:31]4[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]4)[CH:30]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:33]1[CH2:32][CH:31]([N:29]2[CH:30]=[C:26]([NH:25][C:20]3[N:19]=[C:18]([CH2:17][CH2:16][C:15]4[CH:42]=[CH:43][CH:44]=[CH:45][C:14]=4[C:11]4([C:8]([NH2:9])=[O:10])[CH2:12][CH2:13]4)[C:23]([Cl:24])=[CH:22][N:21]=3)[CH:27]=[N:28]2)[CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C4CNC4)c3)ncc2Cl)CC1
Reaction time: 16 h
Yield: 68 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 3-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate A18 (0.110 g, 0.204 mmol) in DCM (5 mL) and the reaction was stirred for 16 hours. The volatiles were removed in vacuo and the resultant residue loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH (100 mL) and then with 5% NH4OH in MeOH (100 mL). The basic fractions were combined and the solvent was removed in vacuo to give the title compound 14 as a tan solid (61 mg, 68%). 1H NMR (400 MHz, d4-MeOD) δ 8.27 (s, 1H), 8.09 (s, 1H), 7.65 (s, 1H), 7.44-7.37 (m, 2H), 7.34 (m, 1H), 7.27 (m, 1H), 5.36-5.18 (m, 1H), 4.15 (m, 2H), 3.96 (m, 2H), 3.20 (m, 4H), 1.63 (m, 2H), 1.20-1.05 (m, 2H). LCMS-C: rt 4.30 min; m/z 438.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]2=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32]Cl)=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1>CN(C=O)C>[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][N:14]3[CH2:15][CH2:16][N:11]([CH2:10][CH:9]=[CH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:12](=[O:18])[C:13]3=[O:17])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1
Reactant: O=C1NCCN(CC=Cc2ccc(Cl)cc2)C1=O
Reactant: Nc1ncnc2cc(CCl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2cc(CN3CCN(CC=Cc4ccc(Cl)cc4)C(=O)C3=O)ccc12
Temperature: 55 °C
Yield: 43.5 %

Procedure:
To a solution of 1-[3-(4-chloro-phenyl)-allyl]-piperazine-2,3-dione (60 mg, 0.23 mmol) in 1.5 mL of DMF is added NaH (10 mg of a 60% dispersion in mineral oil, 0.24 mmol). The mixture is heated at 55° C. for 20 min. To the solution is added 4-amino-7-chloromethyl-quinazoline (49 mg, 0.25 mmol), and the resulting mixture is heated at 55° C. for 20 min as a white precipitate is formed. After this time, reaction mixture is quenched with a few drops of H2O and MeOH, then concentrated. The crude product is purified by RP-HPLC, eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 70% CH3CN/H2O (0.1% TFA) over 30 minutes, and the appropriate product fractions are combined and lyopholized to provide the title compound (56 mg, 0.10 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 9.78 (bs, 2H), 8.83 (s, 1H), 8.40 (s, 1H), 7.72 (d, 1H), 7.65 (s, 1H), 7.49 (d, 2H), 7.38 (d, 2H), 6.61 (d, 1H), 6.30 (dt, 1H), 4.80 (s, 2H), 4.18 (d, 2H), 3.59 (m, 4H). ISP MS, [M+H]+=422.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:17]([O:36][CH3:37])=[CH:18][CH:19]=[C:20]2[C:25]=1[O:24][C:23](=[O:26])[CH:22]=[C:21]2[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=1[Cl:35]>>[Cl:35][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([Cl:34])[C:28]=1[NH:27][C:21]1[C:20]2[C:25](=[C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:8])[CH3:1])[CH3:7])[C:17]([O:36][CH3:37])=[CH:18][CH:19]=2)[O:24][C:23](=[O:26])[CH:22]=1
Reactant: CNCCCN(C)C
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN(C)CCCN(C)C

Procedure:
The title compound was prepared from N1,N1,N3-trimethylpropane-1,3-diamine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 2H), 7.84 (d, 1H), 7.03 (d, 1H), 4.17 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.54 (t, 4H), 2.45 (t, 2H), 2.31 (s, 3H), 2.27 (s, 6H), 1.69 (m, 2H), 1.64 (m, 2H), 1.56 (m, 2H), 1.47 (m, 2H); MS (ESI): 537.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[O:10][C:11]=2[C:12]([F:15])([F:14])[F:13])=[CH:3][CH:2]=1.ClCCl.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>N1C=CC=CC=1>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:9]2[O:10][C:11]([C:12]([F:15])([F:13])[F:14])=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[N:8]=2)=[CH:17][CH:18]=1)=[O:30]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1)c1ccccc1Cl

Procedure:
to a stirred mixture of 4-(4-(pyridin-4-yl)-5-(trifluoromethyl)oxazol-2-yl)benzenamine (214 mg, 701 mop and pyridine, anhydrous (0.567 ml, 7011 μmol) in dichloromethane (5.00 ml, 77709 μmol) at room temperature was added 2-chlorobenzoyl chloride (0.0979 ml, 771 μmol) all at once by metered pipet. The reaction was stirred for an hour then concentrated under reduced pressure, taken up in heptane and concentrated under reduced pressure again. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic separation was dried over magnesium sulfate, filtered and filtrate concentrated under reduced pressure to afford a colorless solid. ESI+ m/z=444.1 [MH]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[NH2:6].[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[C:3]([CH:4]=1)[CH2:2][NH:1][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCS(=O)(=O)c1ccc(N)cc1CN
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(N)cc1CNC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 3-(aminomethyl)-4-(ethylsulfonyl)aniline (1.1 g, 5.1 mmol) in DMF (5 mL) and TEA (2.75 mL) was added benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.4 g, 5.7 mmol) in DCM (15 mL). The solution was stirred for 18 h before quenching with water (25 mL). The reaction mixture was extracted with DCM (2×30 mL), washed with brine and dried (MgSO4). The organic layer was concentrated in vacuo and the residue purified by flash chromatography (0-100% EtOAc/Hexane) to afford 28A (1.0 g, 59%) as an oil. MS (ESI) m/z 349.2 (M+H)+.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:14]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>[OH-].[Na+].O1CCOCC1>[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][N:11]([C:23](=[O:24])[CH2:22][C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)[CH2:10][CH2:9][C:8]=2[N:14]=1
Reactant: Nc1cnc2c(n1)CCNCC2
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cnc2c(n1)CCN(C(=O)Cc1ccc(Cl)cc1)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.8 gm (17.9 mmols) of 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine dihydrobromide were dissolved in 50 ml of 2 N sodium hydroxide, and the solution was admixed dropwise with an ice-cooled solution of 7.5 gm of p-chlorophenyl-acetyl chloride in 50 ml of dioxane. The resulting mixture was stirred overnight and then evaporated, and the residue was extracted with chloroform. The chloroform extract was dried and then evaporated, and the residue was triturated with carbon tetrachloride and suction-filtered.
Reaction SMILES: [CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23][C:24]([CH3:30])([CH3:29])[O:25][C:26](=[O:28])[CH:27]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C3(C#N)CC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23][C:24]([CH3:30])([CH3:29])[O:25][C:26](=[O:28])[CH:27]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:19])[C:16]#[N:17])=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1

Procedure:
The desired product was prepared analogously to example A(86), Step 6, substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-2-methyl-propionitrile (1.25 g, 2.9 mmol) from Step 2 above in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 1.23 g, 99%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1nccc(Nc2ccc3[nH]ncc3c2)n1
Yield: 80 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-aminoindazole (1 mmol) dissolved in 5 ml EtOH was added Et3N (1 mmol). The reaction mixture was refluxed for 5 h. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulted oil was purified by column chromatography to give N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine in a yield of 80%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]1[C:15]([S:16](Cl)(=[O:18])=[O:17])=[C:14]([F:20])[C:13]([F:21])=[C:12]([F:22])[C:11]=1[F:23].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:9][C:10]1[C:11]([F:23])=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=1[S:16]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: COC(C)(C)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(C)(C)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 163 %

Procedure:
To a solution of 3-methoxy-3-methylbutane-1-ol (1.07 g, 9 mmol) and TEA (0.61 g, 6 mmol) in CH2Cl2 (12 mL) was added pentafluorobenzenesulfonyl chloride (0.99 g, 3.7 mmol). The solution was stirred at rt for 2 h. Saturated aqueous NaHCO3 (12 mL) was added to the solution and the mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (75 mL) and washed with 1 M HCl (2×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (2.1 g, 81%). 1H NMR (400 MHz CDCl3) δ 4.42 (t, 2H, J=7.3 Hz), 3.13 (s, 3H), 1.97 (t, 2H, J=7.4 Hz), 1.17 (s, 6H); 19F NMR (400 MHz CDCl3) δ −137.9 (m, 2H), −146.65 (m, 1H), −161.01 (m, 2H). Anal. Calcd. For C12H13F5O4S: C, 41.38; H, 3.76. Found: C, 41.37; H, 3.77.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][CH:7]=1)=[O:16]
Reactant: CC(N)=S
Reactant: CCc1ccc(C(Cl)C(=O)C(=O)OC)cc1
Product: CCc1ccc(-c2sc(C)nc2C(=O)OC)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-ethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.98 min; [M+H]+=262.1.
Reaction SMILES: Cl[CH:2](OC)[CH2:3][CH2:4][CH:5](Cl)OC.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH2:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([N:32]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(N)Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(Cl)CCC(Cl)OC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)n1cccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
1,4-dichloro-1,4-dimethoxybutane (3.30 g) was added to a solution of ethyl 3-(4-benzyloxyphenyl)-2-aminopropionate (3.30 g) in dichloromethane (80 ml) and then amberlyst A-21 (20 g) was added to the mixture. The mixture was stirred at ambient temperature for 18 hours and the reaction mixture was filtered. The filtrate was concentrated and the residue was purified via chromatography on a silica gel column using ethyl acetate/hexane=1/5 as the eluant to afford the desired compound (1.00 g) as a syrup.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13].C(#N)C.P(Cl)(Cl)([Cl:19])=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:19])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cc(Br)c(F)cc12
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Fc1cc2c(Cl)ccnc2cc1Br
Temperature: 90 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
A vial was charged with 7-bromo-6-fluoroquinolin-4-ol (0.460 g, 1.900 mmol) and acetonitrile (9.50 ml). Phosphoryl trichloride (0.354 ml, 3.80 mmol) was then added, and the reaction was stirred for 2 h at 90° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous was extracted once more with ethyl acetate, and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The material was then purified via silica gel chromatography eluting with 0-75% ethyl acetate in heptanes to yield 7-bromo-4-chloro-6-fluoroquinoline (0.141 g, 0.541 mmol, 28.5% yield) as a white solid. m/z (ESI) 260.1 (M+H)+.