Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (10 mg, 0.44 mmol) and triethylamine (91 μL, 0.66 mmol) in methylene chloride (20 mL) was 4-(trifluoromethyl)benzoyl chloride (96 mg, 0.46 mmol) in methylene chloride (5 mL) added dropwise. After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent. Yield: 150 mg (81%) of the title compound as white crystals: mp 203-204° C.; [α]21D−20° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 417 (10, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[OH:31][C@H:32]1[CH2:36][NH:35][C@H:34]([C:37]([OH:39])=[O:38])[CH2:33]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][C@H:32]([OH:31])[CH2:33][C@H:34]5[C:37]([OH:39])=[O:38])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2C[C@H](O)C[C@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-(R)-hydroxy-pyrrolidine-2-(S)-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-(R)-hydroxy-pyrrolidine-2-(S)-carboxylic acid following General Procedure C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[C:25]#[N:26])C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>FC(F)(F)C(O)=O>[C:25]([C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=2)[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:9]=1[OH:8])#[N:26]
Reactant: COC(=O)c1ccnc(-c2ccc(OCc3ccccc3)c(C#N)c2)c1
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1

Procedure:
Methyl 2-[4-(benzyloxy)-3-cyanophenyl]isonicotinate and pentamethylbenzene were heated under reflux in trifluoroacetic acid to obtain methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate. F: 255.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[CH:27]=[C:26]([CH3:28])[NH:25][C:22]4=[N:23][CH:24]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[CH:27]=[C:26]([CH3:28])[N:25]([CH3:39])[C:22]4=[N:23][CH:24]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4[nH]c(C)cc4c3)sc2c1-c1ccc(Cl)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(c3)cc(C)n4C)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate (70 mg, 0.128 mmol) in DMF (5 mL) was added cesium carbonate (54 mg, 0.166 mmol). The reaction solution was stirred at room temperature for 5 minutes, then iodomethane (24 mg, 0.166 mmol) was added. The reaction solution was stirred for 30 minutes and quenched with water. Volatiles were removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C31H32 ClN3O3S: 562.3 (M+H+); Found: 562.3 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](O)=[O:32])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CN.C1C=CC2N(O)N=[N:42][C:40]=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[C:24]([C:31](=[O:32])[NH:42][CH3:40])=[CH:23][N:22]=3)[CH2:19][CH2:20]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(C(=O)O)c(C(F)(F)F)n3)CC2)CC1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: ClCCCl
Solvent: ClCCl
Product: CNC(=O)c1cnc(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Half of the crude 57b was combined with methylamine (0.06 mmol), HOBT (7 mg, 0.06 mmol) and EDC(10 mg, 0.05 mmol) in 1 mL of DCM. The mixture was stirred at room temperature for 18 h, washed with aqueous NaHCO3 and concentrated. The residue was purified by preparative HPLC to afford 57-1: LC-MS 487.3 (MH+), tR=5.20 (Method 5).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:14]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][C:24]([OH:30])=[CH:25][CH:26]=2)[CH:21]=1)(=[O:18])[C:15]([CH3:17])=[CH2:16].C(O)(=O)C(C)=C.C1(C=CC(O)=CC=1)O>C(N(CC)CC)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:30][C:24]2[CH:25]=[CH:26][C:27]3[C:22](=[CH:21][C:20]([O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:29][CH:28]=3)[CH:23]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)Cl)cc1
Reactant: C=C(C)C(=O)Oc1ccc2ccc(O)cc2c1
Agent: C=C(C)C(=O)O
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(C(=O)Oc2ccc3ccc(OC(=O)C(=C)C)cc3c2)cc1
Yield: 95 %

Procedure:
In the same way as described in Example 2, 29.5 g (0.15 mol) of 4-allyloxybenzoyl chloride and 34.5 g (0.15 mol) of 2,7-naphthalenediol monomethacrylate (obtainable in a manner similar to that of the hydroquinone monomethacrylate referred to in Example 2 of U.S. Pat. No. 4,604,342) were reacted with triethylamine as acid scavenger. 7-Methacryloyloxy-2-naphthyl 4-allyloxybenzoate, C22H20O5, with an m.p. of 85° C. was obtained in 95% yield. The 1,4-, 1,5- and 2,6-disubstituted naphthalene derivatives can be prepared in the same way.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:21])=[O:22])=[CH:16][CH:15]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: Clc1ccnc2cc(Br)ccc12
Product: O=S(=O)(O)c1ccc(Nc2ccnc3cc(Br)ccc23)cc1

Procedure:
7-Bromo-4-chloroquinoline and p-aminobenzenesulphonic acid are reacted in a similar manner to that described in Example 14(a) to give 4-(7-bromo-4-quinolylamino)-benzenesulphonic acid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.CC1(C)C(C)(C)OB([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:39][CH:38]=2)O1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:41][CH:42]=3)[C:8]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: COC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 22.7 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.250 g, 0.56 mmol) was reacted with methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.160 g, 0.56 mmol) to afford the title compound (0.058 g, 22%) as a white solid. MW=456.9. 1H NMR (CDCl3, 500 MHz) δ 8.28 (t, J=1.2 Hz, 1H), 8.30-8.26 (m, 1H), 7.52-7.45 (m, 3H), 7.42-7.37 (m, 1H), 7.23 (d, J=8.0 Hz, 2H), 4.60 (s, 2H), 3.67 (s, 3H), 3.60 (s, 2H), 3.50-3.45 (m, 2H), 3.18 (t, J=6.5 Hz, 2H), 2.54-2.48 (m, 2H); APCI MS m/z 457 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CS([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=1)(=O)=O.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)nc1
Yield: 55 %

Procedure:
To 18.4 g of 4-bromophenol dissolved in a 80 ml THF/80 ml DMSO mixture was added 13.1 g of t-BuOK and then 25.0 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled overnight and then poured into 3 volumes of water and stirred. The pink-white crystalline product was filtered, dissolved in CH2Cl2 and dried over MgSO4. Recrystallization from ethanol gave purified 2-(4-bromophenoxy)-5-(methylsulfonyl)pyridine, (55% yield), as white shiny needles, m.p. 125°-126° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[NH:8][C:9]2[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:10]=2[N:11]=1.O(Cl)Cl.O.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[CH:26]([C:6]1[N:2]([CH3:1])[C:3]([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:9]=3[N:8]=2)=[CH:4][CH:5]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: Cn1cccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: ClOCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(C=O)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of 2-(1-methylpyrrol-2-yl)-5,6-dichlorobenzimidazole (65 mg, 0.24 mmol) in dimethylformamide (2 mL) was added phoshorus oxychloride (0.067 mL, 0.72 mmol), and the mixture was stirred at room temperature for 24 h. Water and aqueous sodium hydroxide (1.0 mol/L) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 2-(2-formyl-1-methylpyrrol-5-yl)-5,6-dichlorobenzimidazole (50 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:22]([C:29]1[O:33][C:32]([NH2:34])=[N:31][N:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:22]([C:29]1[O:33][C:32]([NH:34][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:10]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:2]=2[Cl:1])=[N:31][N:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COCC(F)(F)F
Reactant: Nc1nnc(Cc2ccccc2)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)Nc2nnc(Cc3ccccc3)o2)c(Cl)c1COCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
90 mg (0.26 mmol) of 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzoic acid and 45 mg (0.26 mmol) of 5-benzyl-1,3,4-oxadiazol-2-amine are dissolved at room temperature (RT) in 8 ml of CH2Cl2. Then 248 mg (0.398 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added, the mixture is stirred at RT for one hour and then 0.181 ml (1.3 mmol) of triethylamine, 6 mg (0.052 mmol) of 4-dimethylaminopyridine are added. Then the mixture is stirred at RT for 20 h and washed twice with 4 ml each time of water, dried over Na2SO4 and concentrated. The residue is purified by column chromatography (prep. HPLC; acetonitrile/water). Yield 70 mg (45%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[Br:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Nc1ccc2ccc(-c3cccc(Br)c3)nc2n1
Solvent: CCCO
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3cccc(Br)c3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 56.9 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.2 g), N,N'-carbonyldiimidazole (1.8 g) and 2-amino-7-(3-bromophenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (3.1 g; m.p. approximately 140° C.) is dissolved in boiling propanol (100 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with propanol (2×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(3-Bromophenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (2.2 g), m.p. 144°-146° C., is obtained.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][N:7]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[C:6](=[O:23])[N:5]1[C:24]1[CH:29]=[CH:28][N:27]2[N:30]=[CH:31][C:32]([C:33]3[CH:38]=[CH:37][C:36]([C:39]4[N:43]=[CH:42][N:41](COCC[Si](C)(C)C)[N:40]=4)=[CH:35][CH:34]=3)=[C:26]2[N:25]=1)([CH3:3])[CH3:2].CCO.C([O-])(O)=O.[Na+].[ClH:60]>CCOCC>[ClH:60].[NH:41]1[CH:42]=[N:43][C:39]([C:36]2[CH:35]=[CH:34][C:33]([C:32]3[CH:31]=[N:30][N:27]4[CH:28]=[CH:29][C:24]([N:5]5[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][N:7]([CH2:9][CH:10]6[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]6)[C:6]5=[O:23])=[N:25][C:26]=34)=[CH:38][CH:37]=2)=[N:40]1
Reactant: CC(C)[C@H]1CN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)[C@H]1CN(CC2CCNCC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1

Procedure:
A mixture of (S)-tert-butyl 4-((4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)methyl)piperidine-1-carboxylate (99 mg, 0.14 mmol) and EtOH/6N aqueous HCl (1:2, 2 mL total) was heated at reflux for 2 hours. After cooling, the reaction mixture was neutralized by slow addition of saturated aqueous NaHCO3 solution. The mixture was extracted with 10% THF in dichloromethane. The combined extracts were washed with brine, dried and concentrated. The residue was purified by column chromatography (20% 7N ammonia in MeOH/dichloromethane) to give the free base, which was converted to HCl salt (38 mg, 53%) by treatment with 2N HCl in ether. LCMS (APCI+) m/z 486.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccc(F)cc2nc1Cl
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C/c1cc2ccc(F)cc2nc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 2-chloro-7-fluoroquinoline-3-carboxaldehyde (6.3 g, 30 mmol) in dry THF (200 mL) under nitrogen was added titanium(IV) isopropoxide (17.0 g, 60 mmol) and the reaction mixture stirred at r.t. for 10 minutes. (R)-(−)-2-Methyl-2-propane-sulfinamide (3.6 g, 30 mmol) was added to the reaction mixture, which was stirred at r.t. for 72 h and partitioned between water (20 mL) and DCM (150 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the title compound (7.2 g, 76%) as a pale yellow solid. δH (CDCl3) 9.09 (1H, s), 8.83 (1H, s), 7.96 (1H, dd, J=6.0 Hz), 7.69 (1H, d, J=7.2 Hz), 7.42 (1H, t, J=8.4 Hz), 1.32 (9H, s).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:36]3[CH:37]=[N:38][CH:39]=[C:40]([C:41]#[N:42])[CH:43]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a white solid. UPLC-MS (Condition 3) tR=1.02 min, m/z=486.2 [M+H]+, m/z=530.0 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.85 (d, J=11.42 Hz, 1H) 3.16-3.26 (m, 2H) 3.35-3.43 (m, 1H) 4.20 (br. s, 1H) 4.90 (d, J=3.64 Hz, 1H) 7.35 (d, J=9.16 Hz, 2H) 7.82-7.89 (m, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.41 (t, J=2.07 Hz, 1H) 8.79 (d, J=2.38 Hz, 1H) 8.90 (d, J=2.26 Hz, 1H) 9.03 (d, J=1.88 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([F:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].C1COCC1>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([F:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3F)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3F)c(=O)n(C)c2n1
Yield: 36 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2,4-difluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (80 mg, 0.160 mmol) and 2.00N methylamine in THF (0.9 mL, 1.80 mmol) were combined to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2,4-difluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (31 mg, 36% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.53 (s, 9H), 2.90 (s, 3H), 3.52-3.59 (m, 3H), 7.31-7.38 (m, 2H), 7.78-7.90 (m, 3H), 8.12-8.16 (m, 1H), 8.48 (s, 1H), 8.63-8.70 (m, 1H), 8.65 (s, 1H); MS (ESI) m/z: 483.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:28])=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1cc[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In benzene (4 ml) was dissolved 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (272 mg), and to the solution was added m-chloroperbenzoic acid (267 mg). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (70 ml), saturated sodium hydrogen carbonate solution (30 ml) and sodium nitrite (100 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried to give 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (205 mg) as pale yellow crystals.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC
Yield: 35.5 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.1 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(3,4-dimethoxyphenyl)-1-hexanone (1.0 g) were reacted and treated in the same manner as in Example 172 to give 0.56 g of 4-amino-5-chloro-N-((1-(6-(3,4-dimethoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NCc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A solution of (3-benzylamino-phenyl)-carbamic acid tert-butyl ester (1.27 g, 4.3 mmol), benzenesulphonyl chloride (1.79 ml, 14 mmol) and pyridine (1.24 ml, 15.3 mmol) in dry dichloromethane (30 ml) were heated to reflux for 15 hrs. The reaction mixture was cooled to room temperature and quenched with water and extracted with dichloromethane (3×75 ml). The combined organics were dried (magnesium sulphate), concentrated in vacuo and the crude residue purified by flash column chromatography (SiO2) eluting with dichloromethane to afford the title compound as a brown oil (1.09 g, 58%). HPLC retention time 6.6 mins.