Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5]C1C=CC=CC=1CN(CC1C=CC=CN=1)CCCN1CCC(C2C=CC=CC=2)CC1)([CH3:4])([CH3:3])[CH3:2].[CH2:36]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[C:49]([O:53][C:54]1[CH:74]=[CH:73][CH:72]=[CH:71][C:55]=1[CH2:56][N:57]([CH2:67][CH2:68][CH2:69]Cl)[CH2:58][CH2:59][NH:60][C:61](=[O:66])C(C)(C)C)([CH3:52])([CH3:51])[CH3:50].C([O-])([O-])=O.[K+].[K+]>>[CH2:36]([CH:43]1[CH2:48][CH2:47][N:46]([CH2:69][CH2:68][CH2:67][N:57]([CH2:56][C:55]2[CH:71]=[CH:72][CH:73]=[CH:74][C:54]=2[O:53][C:49]([CH3:50])([CH3:51])[CH3:52])[CH2:58][CH2:59][NH:60][C:61](=[O:66])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(C)(C)Oc1ccccc1CN(CCCCl)CCNC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCCN(CCCN1CCC(Cc2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Yield: 80 %

Procedure:
The same procedure as described for compound 20 was applied to 4-benzylpiperidine (0.46 g, 2.63 mmol), compound 23 (0.7 g, 1.75 mmol), KI (0.87 g, 5.25 mmol) and K2CO3 (1.21 g, 8.75 mmol). The residue was purified on a silica gel TLC plate that was developed in 5% methanolic NH3 (7 M NH3 in methanol/95% CH2Cl2. The product was isolated as yellow oil (80% yield). 1H NMR (CDCl3) δ 7.373 (d, 1H, Ar), 7.264 (m, 2H, Ar), 7.176 (t, 1H, Ar), 7.137 (d, 2H, Ar), 7.137 (d, 2H, Ar), 7.108 (d, 1H, Ar), 7.021 (dd, 1H, Ar), 6.985 (t, 1H, Ar), 3.577 (s, 2H, —CH2—), 3.167 (d, 2H, —CH2—), 2.892 (d, 2H, —CH2—), 2.524 (d, 2H, —CH2—), 2.498 (t, 2H, —CH2—), 2.453 (t, 2H, —CH2—), 2.290 (t, 2H, —CH2—), 1.839 (t, 2H, —CH2—), 1.657 (m, 2H, —CH2—), 1.618 (d, 2H, —CH2—), 1.517 (m, 1H, —CH—), 1.426 (s, 9H, —C(CH3)3, 1.376 (s, 9H, —C(CH3)3, 1.329 (overlapped m, 4H). Mass Spec.=538.77 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].[CH4:4].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1)([O-:7])=[O:6].O>CN(C)C=O>[CH3:4][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=2)=[C:15]1[C:23]([NH2:25])=[O:24]
Reactant: C
Reactant: NC(=O)c1[nH]c2ccccc2c1-c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C(N)=O)c(-c2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.047 g of sodium hydride and then 73 μl of methane iodide are added to a solution of 0.3 g of 3-(4-nitro-phenyl)-1H-indole-2-carboxamide in 8 ml of anhydrous dimethylformamide under argon. The reaction mixture is stirred at ambient temperature for 2 hours and 45 ml of water are added. The solid formed is filtered off, washed with 3 times 15 ml of water, and filter-dried. After drying under vacuum, 0.22 g of 1-methyl-3-(4-nitrophenyl)-1H-indole-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=2[O:22][CH3:23])[CH:6]=[CH:5][C:4]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[Br:17][C:15]1[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([O:22][CH3:23])=[C:11](/[CH:10]=[CH:9]/[C:7]2[CH:6]=[CH:5][C:4]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:3]([CH:8]=2)[CH2:2][NH:1][C:35](=[O:37])[CH3:36])[CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)c(CN)c2)cc(Br)cc1C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)c(CNC(C)=O)c2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
step 2—To a solution of 210 (0.150 g, 0.321 mmol), pyridine (100 L) and DCM (10 mL) cooled to 0° C. was added acetic anhydride (70 μL). The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was diluted with DCM, washed with sat'd. CuSO4 and twice with 1N HCl, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (50 to 75% EtOAc) to afford 45 mg of N-{5-[(E)-2-(5-bromo-3-tert-butyl-2-methoxy-phenyl)-vinyl]-2-methanesulfonylamino-benzyl}-acetamide (212).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])[CH:2]=[CH2:3].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][O:14][Si:19]([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the diol 14 (16.97 g, 84 mmol) in CH2Cl2 (235 mL) was treated with TEA (11.7 mL, 8.5 g, 84 mmol) and stirred for 15 minutes at room temperature. TBDMSCl (9.72 g, 64 mmol) and DBU (16.8 mmol, 2.51 mL, 2.56 g) were added and the reaction mixture stirred for a further 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with saturated NH4Cl (160 mL), brine (160 mL), dried (MgSO4), filtered and evaporated in vacuo to give an oil which was a mixture of the required product (major component), unreacted diol and the presumed disilyated compound by TLC (50% EtOAc/Petroleum Ether). Flash chromatography (20-100% EtOAc/Petroleum Ether) isolated the 3 components, to provide the monosilylated compound 15 as a slightly yellow transparent oil (13.85 g, 52%): [α]21D=−58.6° (c=1.14, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ 6.01-5.86 (m, 1H, NCO2CH2CH═CH2), 5.34-5.18 (m, 2H, NCO2CH2CH═CH2), 4.59-4.49 (m, 3H, NCO2CH2CH═CH2 and NCHCH2OTBDMS), 4.06-3.50 (m, 5H, NCH2CHOH, NCH2CHOH and NCHCH2OTBDMS), 2.20-2.01 (m, 2H, NCH2CHOHCH2), 0.87 (s, 9H, SiC(C3)2), 0.0 (s, 6H, Si(CH3)2); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ 155.0 (NC═O), 133.1 (NCO2CH2CH═CH2), 117.6 and 117.1 (NCO2CH2CH═CH2), 70.3 and 69.7 (NCH2CHOH), 65.9 and 65.6 (NCO2CH2CH═CH2), 63.9 and 62.8 (NCHCH2OTBDMS), 57.8 and 57.4 (NCHCH2OTBDMS), 55.7 and 55.2 (NCH2CHOH), 37.3 and 36.6 (NCH2CHOHCH2), 25.9 (SiC(CH2)2), 18.2 (SiC(CH3)3), −5.5 (Si(CH3)2); MS (EI), m/z (relative intensity) 316 (M+.+1, 29), 315 (M+., 4), 300 (M-CH3, 26), 284 (4), 261 (8), 260 (50), 259 (100), 258 (M-OC3H3 or M-tBu, 100), 218 (13), 215 (10), 214 (52), 200 (12), 170 (M-CH2OTBDMS, 100), 156 (40), 126 (58), 115 (33), 108 (41), 75 (35); IR (Neat) 3422 (br, OH), 2954, 2858, 1682 (C═O), 1467, 1434, 1412 (SiCH2), 1358, 1330, 1255 (SiCH2) 1196, 1180, 1120, 1054, 995, 919, 837, 776, 669 cm−1; exact mass calcd for C15H29NO4Si m/e 315.1866, obsd m/e 315.1946.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.CCCCCC.C(OCC)(=O)C>CO.[C].[Pd]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
To a solution of a crude product of t-butyl 4-[4-(2-fluoro-4-nitrophenoxy)pyridin-2-ylcarbamoyl]piperidine-1-carboxylate (548 mg) in methanol (50 ml) was added 10% palladium carbon (100 mg), followed by stirring under a hydrogen atmosphere at room temperature for 2 hrs. The catalyst was filtered. The filtrate was concentrated under a reduced pressure to give a residue, which was then subjected to silica gel column chromatography (Fuji Silysia BW-300, eluent; hexane:ethyl acetate=1:1 to 1:2, then ethyl acetate) to provide a mixture of the starting material and the target compound. The mixture was dissolved in methanol (50 ml) again, and then 10% palladium carbon (100 mg) was added thereto, followed by stirring under a hydrogen atmosphere at room temperature for 2 hrs. The catalyst was filtered. The filtrate was concentrated under a reduced pressure to give a residue, which was then filtered by silica gel. The filtrate was concentrate under a reduced pressure to provide the titled compound (185 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[N:5]=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])C.[CH:18](O)=[O:19].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH:11]([NH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][O:10][CH:18]=[O:19])[N:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: Nc1ccnn1CCCO
Reactant: CC(=O)OC(C)=O
Reactant: O=CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccnn1CCCOC=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Amino-1-(3-hydroxypropyl)pyrazole (5.3 g) was added to a mixture of acetic anhydride (8.86 ml) and formic acid (7.08 ml) under ice-cooling. The mixture was stirred for two hours at room temperature. The reaction mixture was added to a mixture of ice-water (30 ml), ethyl acetate (30 ml) and tetrahydrofuran (60 ml), and an aqueous solution of potassium carbonate was added thereto to adjust the pH of the mixture to 7. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 5-formamido-1-(3-formyloxypropyl)pyrazole (6.74 g).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH2:16]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH3:13])#[N:2]
Reactant: CC(C)(C)CN
Reactant: COC(=NC#N)c1ccccn1
Solvent: CO
Product: CC(C)(C)CN=C(NC#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 2,2-dimethylpropylamine (0.30 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.63 g, 2.9 mmol, yield: 94%) as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:23][CH2:22][CH2:21][O:20][CH3:19])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COCCN
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: COCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and 2-methoxyethanamine, the title compound was obtained; MS (Found M+1=317).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[CH:33]1[CH:34]=[CH:35][C:36]2[N:41]([OH:42])[N:40]=[N:39][C:37]=2[CH:38]=1.[H-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[N:41]1([O:42][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[C:8](=[C:18]4[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:20][CH2:19]4)[C:9]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=4[CH2:11][CH2:12][C:3]=23)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=2[N:39]=[N:40]1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Reactant: On1nnc2ccccc21
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(On4nnc5ccccc54)ccnc32)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The 4,8-dichloro compound from Example 250 (0.8 grams) was added to a solution of HOBT (1.2 grams) and sodium hydride (0.14 grams, 60% in mineral oil) in anhydrous dimethyl-formamide (60 mL). The resulting solution was irradiated with a 200 W lamp while stirring at 25° C. for 60 hours. The solution was poured into 1N aqueous NaOH while stirring and an additional 400 mL of water was added to the resulting mixture. Filtration provided a solid which was washed with water several times. The solid was dissolved in CH2Cl2-acetone, dried over anhydrous MgSO4, and concentrated in vacuo to proved the title compound (0.87 grams, 90%, mp=120-122° C., MH+ 563).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:22]=2)[C:10]=1[CH3:35])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[CH3:35][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:22]=1
Reactant: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(COc2cccc(OCC3CCOCC3)c2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a solution of 4-(benzyloxy)-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (330 mg) in ethanol-THF (1:1, 10 mL) was added 10% palladium-activated carbon (80 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-4(1H)-one (207 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[C:21](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][CH:10]2[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[C:16]([CH3:21])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(F)ccc1NC1CN(C(=O)OC(C)(C)C)C1
Yield: 67.2 %

Procedure:
A solution of 1-Boc-3-azetidinone (800 mg, 4.67 mmol), 4-fluoro aniline (0.519 ml, 4.67 mmol), acetic acid (0.535 ml, 9.34 mmol) and sodium(triacetoxy)borohydride (1.98 g, 9.34 mmol) in 1,2-dichloroethane (20 ml) was stirred under N2 atmosphere at room temperature for 1 day. Sat. solution of NaHCO3 (25 ml) was added. After phase separation, the aqueous layer was extracted with dichloromethane (2×35 ml). The collected organics after solvent evaporation were purified by Biotage SNAP-Si cartridge (25 g) eluting with cyclohexane/ethylacetate from 90/10 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D30) (880 mg)
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][NH:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[C:26]([F:32])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=3)[CH2:18][CH2:17]2)[N:12]=[C:11]([O:36][CH3:37])[N:10]=1)(C)(C)C.[Li+].[OH-].O.Cl>C1COCC1.CO>[CH2:34]([O:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([O:29][CH2:30][CH3:31])[C:26]=1[F:32])[CH2:22][N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:13]2[N:12]=[C:11]([O:36][CH3:37])[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:38])=[O:5])[N:14]=2)[CH2:17][CH2:18]1)[CH3:35]
Reactant: CCOc1cc(CN2CCC(Nc3nc(NCC(=O)OC(C)(C)C)nc(OC)n3)CC2)cc(OCC)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(CN2CCC(Nc3nc(NCC(=O)O)nc(OC)n3)CC2)cc(OCC)c1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
To a stirred solution of {4-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-6-methoxy-[1,3,5]triazin-2-ylamino}-acetic acid tert-butyl ester (0.09 g, 0.2 mmol, 1.0 equiv; example 297) in THF/methanol (1:1) (4 mL) was added drop by drop a 1 M solution of LiOH in water (0.42 mL, 0.42 mmol, 2.1 equiv). After 16 h, the reaction mixture was poured into ice water, the pH adjusted to 3-4 with diluted HCl and the mixture extracted three times with dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure to yield 0.031 g (32%) of the title compound as a colorless solid. MS (ISN): 477.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1C)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)=[O:6].Cl[C:22]1[C:27]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)=[CH:26][CH:25]=[CH:24][N:23]=1.N(CC)(CC)CC.FC(C(O)=O)(F)F>CS(C)=O>[CH3:16][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([NH:1][C:22]3[C:27]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:3]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:15]
Reactant: Clc1ncccc1-c1ccncn1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)c1cccc(NC(=O)c2cccc(Nc3ncccc3-c3ccncn3)c2)c1
Temperature: 90 °C
Reaction time: 22 h

Procedure:
To 3-amino-N-(3-isopropyl-phenyl)-4-methyl-benzamide (300 mg, 1.2 mmol), 4-(2-chloropyridin-3-yl)pyrimidine (100 mg, 0.52 mmol) and DMSO (0.15 mL) was added NEt3-TFA (0.11 mL). The resulting slurry was stirred for 22 hours at 90° C. The crude material was purified by silica gel chromatography (40-60% EtOAc/hexanes) to yield the title compound as a yellow solid. MS m/z=410 [M+1]+. Calc'd for C25H23N5O: 409.49.
Reaction SMILES: O=[C:2]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[S:4](=[O:11])(=[O:10])[NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].[ClH:26]>N1C=CC=CC=1>[ClH:26].[S:4]1(=[O:11])(=[O:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:2](=[S:13])[NH:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NS(=O)(=O)c2ccsc21
Agent: Cl
Solvent: c1ccncc1
Product: O=S1(=O)NC(=S)c2sccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 15.2 g (0.08 mole) of 2,3-dihydro-3-oxothieno[2,3-d]isothiazole 1,1-dioxide (U.S. Pat. No. 4,028,373) in 200 ml of dry pyridine at 80° C. was added 15.2 g of phosphorus pentasulfide over a period of 10 minutes. The reaction mixture was stirred for a period of 45 minutes at this temperature and was then poured into 500 ml of ice water. The reaction mixture was acidified with conc. hydrochloric acid solution to pH 1. The resulting precipitate was collected on a filter and was dissolved in 20% sodium bicarbonate solution then filtered. The filtrate upon acidification with conc. hydrochloric acid gave 7.6 g of thieno[2,3-d]isothiazole-3(2H)-thione 1,1-dioxide, m.p. 185°-187° C. A second treatment of the precipitate which did not dissolve with 20% sodium bicarbonate followed by acidification gave an additional 3.7 g of product, m.p. 186°-189° C. The two crops of product were combined giving 11.3 g (69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from [5-(isobutyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example C38) (5.28 g, 13.99 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a pale yellow solid (3.69 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][NH:26][CH2:27][C:28]([F:29])([F:30])[F:31])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: O=C(O)c1ccc(CNCC(F)(F)F)cc1Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNCC(F)(F)F)cc1Cl

Procedure:
To 24.9 g of 2-chloro-4-(methoxycarbonyl)benzoic acid and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at −78° C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to −78° C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was was cooled to 0° C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction is re-cooled to 0° C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0° C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45° C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12]
Reactant: O=Cc1cccc(O)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(Oc2nccs2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
In a sealed tube, combine 2-bromo-thiazole (2.0 ml, 22.2 mmol), 3-hydroxy-benzaldehyde (1.8 g, 15.0 mmol) and potassium carbonate (2.1 g, 15.0 mmol) in dimethylformamide (20 ml). Heat to 100° C. After 48 hours, cool, pour into water (150 ml), and extract with ether. Combine the organic layers and wash sequentially with distilled water and brine and then dry, (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the title compound.