Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C[O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[O:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19](=[O:30])[C:18]=2[CH:17]=1)=[O:15])=[O:6].[OH-].[Na+]>O>[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[O:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19](=[O:30])[C:18]=2[CH:17]=1)=[O:15])([OH:6])=[O:4]
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc2oc3c(c(=O)c2c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccccc1C(=O)O)c1ccc2oc3c(c(=O)c2c1)CCCC3
Yield: 71.8 %

Procedure:
To 80 ml of a methanol suspension containing 4.31 of N-(2'-methoxycarbonylphenyl)-5,6,7,8tetrahydro-9-oxo-xanthene-2-carboxylic acid amide obtained in Example 43 was added 10 ml of an aqueous solution containing 0.48 g of sodium hydroxide. The mixture was heated for 3 hours under refluxing and stirring conditions. The solvent was then removed by distillation to give a residue which was dissolved in hot water and filtered. The filtrate was acidified with concentrated hydrochloric acid to separate a yellowish white deposit. The deposit was collected by filtration, washed with water and then air-dried. Finally, the deposit was recrystallized from acetic acid to obtain 2.96 g (yield: 71.8%) of N-(2'-carboxyphenyl)-5,6,7,8-tetrahydro-9-oxo-xanthene-2-carboxylic acid amide.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O.O>[CH:17]1[C:18]2[CH:6]([CH2:5][O:4][C:2]([CH:20]([NH2:19])[CH2:21][CH2:22][CH2:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][CH:25]=3)=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCCC(N)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
9-Fluorenylmethyl chloroformate (6.9 g) was added to biphasic mixture of tert-butyl 4-(4-aminobutyl)benzoate (5.7 g) in THF (100 mL) and saturated aqueous NaHCO3 (50 mL). The resulting mixture was stirred at r.t. for 1 h and then diluted with EtOAc and H2O. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography to give 7.4 g of tert-butyl 4-(4-(9-fluorenylmethoxycarbonyl)-aminobutyl)benzoate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1>>[CH3:19][C:15]1[CH:14]=[C:13]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1cccc(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with m-toluidine to yield 2-[(3-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:13]([O:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl>N1C=CC=CC=1>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[C:5]([N:25]1[C:26]([CH3:28])=[CH:27][C:23]([O:22][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:15][N:14]=2)=[N:24]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)nn1C(=O)N(C(C)C)C(C)C
Temperature: 80 °C
Yield: 86.5 %

Procedure:
A solution of diisopropylcarbamoyl chloride (1.47 g, 9.0 mmol) in pyridine (5 ml) was added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (1.67 g, 6.0 mmol) in pyridine (10 ml), and the mixture was stirred under heating at 80° C. for 20 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N,N-diisopropyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (2.1 g, yield: 86.7%). mp: 58-60° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.28 (d, J=7.5 Hz, 12H), 2.29 (s, 3H), 3.50-4.10 (m, 2H), 6.00 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 8.31 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[CH2:13][CH2:12][N:11]([C:14](OCC)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(Cl)Cl.[OH-].[Na+]>[CH3:14][N:11]1[CH2:12][CH2:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=2)([CH3:19])[CH2:9][CH2:10]1
Reactant: CCOC(=O)N1CCC(C)(c2ccc(N)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCC(C)(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
To a solution of ethyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (444 mg, 1.692 mmol) in THF (10 mL) was added solid LAH (321 mg, 8.46 mmol) portion-wise. The formation of bubbles were observed during addition. The reaction mixture was stirred at room temperature for 20 min. The reaction mixture was diluted with methylene chloride and 15 mL of 1N NaOH was added slowly to destroy excess LAH. The resulting mixture was separated by separatory funnel. The organic layer was washed with water and concentrated. The residue was purified by MPLC (ISCO, 6% ammonia/MeOH/CH2Cl2, 40 g silica gel column) to give 267 mg colorless oil. (M+H)+=205.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[S:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:42][C:43]1[CH:44]=[C:45]([C@H:49]([NH2:51])[CH3:50])[CH:46]=[CH:47][CH:48]=1>CN(C=O)C.CCOC(C)=O.O>[Cl:42][C:43]1[CH:44]=[C:45]([C@H:49]([NH:51][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([S:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:5]=2)[CH3:50])[CH:46]=[CH:47][CH:48]=1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N[C@H](C)c2cccc(Cl)c2)cc1S(=O)(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 4-methoxy-3-(morpholinosulfonyl)benzoic acid 42 (0.824 g, 2.73 mmol) in DMF (6 mL) was added EDCI (0.686 g, 3.58 mmol) and HOBT (0.536 g, 3.50 mmol), the solution was stirred for 30 min and (R)-1-(3-chlorophenyl)ethanamine (0.673 g, 4.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc and water. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 60% to 100% EtOAc in hexanes) gave (R)—N-(1-(3-chlorophenyl)ethyl)-4-methoxy-3-(morpholinosulfonyl)benzamide 43 (1.14 g, 95.0% yield) as a white solid. Mass spectrum: calculated for C20H23ClN2O5S 438.1. found 439.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.Cl[C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:19]=[C:18]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=3[N:30]=[C:29]2[CH:39]([F:41])[F:40])[N:17]=1>C1COCC1.C(O)(=O)C.O>[F:41][CH:39]([F:40])[C:29]1[N:28]([C:18]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:21]=[C:16]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[O:8][CH3:9])[N:17]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=2[N:30]=1
Reactant: COc1ccncc1N
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccncc1Nc1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3c(OC)cccc32)n1
Reaction time: 0.25 h
Yield: 41.9 %

Procedure:
To a solution of 0.121 g (0.98 mmol) of 3-amino-4-methoxypyridine in THF (3 mL) was added 0.44 mL of butyllithium (2.5 M solution in hexanes), and the mixture stirred for 15 min. A solution of 0.128 g (0.32 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (8:2) and then with CH2Cl2/EtOAc (2:1) to CH2Cl2/EtOAc (1:1) gave a yellow powder. Recrystallization from ethanol/CH2Cl2 gave 0.065 g (42% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 239-241° C.; 1H NMR (CDCl3) δ9.43 (br s, 1H), 8.31 (d, J=5.6 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.54 (t, JHF=53.4 Hz, 1H), 7.39-7.35 (m, 2H), 6.89 (d, J=5.6 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.94 (s, 4H), 3.82-3.80 (m, 4H); Anal. Calcd. for C22H22F2N8O3: C, 54.5; H, 4.6; N, 23.1. Found: C, 54.4; H, 4.5; N, 22.9%.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[OH:23][C@H:24]([CH2:27][OH:28])[CH2:25][NH2:26]>CC(O)C>[OH:23][C@H:24]([CH2:27][OH:28])[CH2:25][NH:26][C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C#N)c(-c3cccc(F)c3)c2c1
Reactant: NC[C@H](O)CO
Solvent: CC(C)O
Product: COc1ccc2nc(NC[C@H](O)CO)c(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 12 h

Procedure:
A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (65.0 mg, 0.208 mmol) and (S)-2,3-dihydroxypropylamine (114 mg, 1.25 mmol) in 10 mL of 2-propanol was heated in a sealed tube at 120° C. for 63 hours. Another portion of (S)-2,3-dihydroxypropylamine was added (50 mg), and the reaction was stirred for another 12 hours. The solution was concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C20H19FN3O3 (M+H+): 368.1405. Found 368.1398.
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].N#N.C1OC1CO.Cl>CS(C)=O.OCC(CO)O>[C:8]([OH:10])(=[O:9])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cl
Agent: N#N
Agent: OCC1CO1
Solvent: OCC(O)CO
Solvent: CS(C)=O
Product: O=C(O)C=Cc1ccccc1
Reaction time: 2 h

Procedure:
8.719 g of p-hydroxy cinnamic acid was dissolved in 10 ml of DMSO, and 100 mg of sodium hydroxide was added. The mixture was stirred and heated to 90° C. under a flow of N2 gas. 19.7 g of glycidol was added gradually, heating and agitation was carried out for 2 hours, neutralized by adding hydrochloric acid and then the adduct of cinnamic acid and glycerin was obtained.
Reaction SMILES: [C:1]1([C:7]([CH2:13][C:14]#[N:15])=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:20]([CH2:29][CH2:30]CC)[C:21]1[CH:26]=[CH:25][C:24]([N:27]=O)=[CH:23][CH:22]=1)[CH2:17]CC>>[CH2:29]([N:20]([CH2:16][CH3:17])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:13]([C:14]#[N:15])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:23][CH:22]=1)[CH3:30]
Reactant: CCCCN(CCCC)c1ccc(N=O)cc1
Reactant: N#CCC(=C(C#N)C#N)c1ccccc1
Product: CCN(CC)c1ccc(N=C(C#N)C(=C(C#N)C#N)c2ccccc2)cc1

Procedure:
The above procedure was used for the preparation of 3-[[4-dibutylamino)phenyl]imino]-2-phenyl-1-propene-1,1,3-tricarbonitrile using N,N-dibutyl-4-nitrosoaniline in place of N,N-diethyl-4-nitrosoaniline.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=C[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.[N:37]1C=CN=CC=1C(O)=O>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:37][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccc(F)cc2F)cn1
Reactant: O=C(O)c1cnccn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccc(F)cc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2,4-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 229 and pyrazine-2-carboxylic acid.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.[Br:27][C:28]1[C:29]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)=[N:30][C:31](Cl)=[N:32][CH:33]=1.C1COC2C=CC(N)=CC=2O1>>[Br:27][C:28]1[C:29]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)=[N:30][C:31]([NH:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)=[N:32][CH:33]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2Br)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2c(c1)OCCO2
Product: Oc1cccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2Br)c1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 5-bromo-2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield 5-bromo-N2-(3,4-ethylenedioxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 9.33 (s, 1H), 9.06 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.13-7.06-(m, 4H), 6.94 (bs, 1H), 6.61 (d, 1H, J=8.7 Hz), 6.54-6.50 (m, 1H), 4.17-4.13 (m, 4H); LCMS: ret. time: 20.01 min.; purity: 93%; MS (m/e): 416 (MH+).
Reaction SMILES: C[O:2][P:3]([CH:7]=[CH:8][CH:9]1[CH:13]([O:14][Si](CC)(CC)CC)[CH:12]([F:22])[CH:11]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:10]1)(=[O:6])[O:4]C.[N:41]1C(C)=CC=CC=1C.C[Si](Br)(C)C.C(N(CC)CC)C.[F-].[NH4+]>CC#N.CO.CN(C=O)C>[NH4+:23].[NH4+:41].[C:33]([NH:32][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[C:29]=1[N:30]=[CH:31][N:23]2[CH:11]1[O:10][CH:9]([CH:8]=[CH:7][P:3](=[O:2])([O-:4])[O-:6])[CH:13]([OH:14])[CH:12]1[F:22])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC[Si](CC)(CC)OC1C(C=CP(=O)(OC)OC)OC(n2cnc3c(NC(=O)c4ccccc4)ncnc32)C1F
Reactant: Cc1cccc(C)n1
Agent: C[Si](C)(C)Br
Agent: [F-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Nc1ncnc2c1ncn2C1OC(C=CP(=O)([O-])[O-])C(O)C1F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
Compound 56.2 (338 mg, 0.57 mmol) in CH3CN (6.0 mL) was treated with 2,6-lutidine (662 μL, 5.7 mmol) and TMSBr (368 μL, 2.9 mmol) at 0° C. for 30 min. The mixture was warmed to r.t. and stirred for 30 min. The mixture was cooled to −40° C. and treated with triethylamine (794 μL, 5.7 mmol) in MeOH (2 mL). The mixture was warmed to r.t. and concentrated in vacuo. The residue in DMF (2.0 mL) was treated with ammonium fluoride (1.06 g, 28.5 mmol) and heated to 80° C. for 5 h. The solvent was removed in vacuo and residue was subjected to reverse phase HPLC eluting with 5-50% CH3CN-water gradient to give 56.3 (76 mg, 30% yield, 2 steps): white solid; 1H NMR (CD3OD, 300 MHz) 8.71 (s, 1H), 8.49 (s, 1H), 6.75 (d, J=8.1 Hz, 2H), 7.61 (app t, J=6.6 Hz, 1H), 7.52 (m, 2H), 6.71 (m, 2H), 6.15 (t, J=18.3 Hz, 1H), 5.17 (d, J=52.5 Hz, 1H), 4.50 (m, 2H); 31P NMR (D2O 121.4 MHz) 12.2; 19F NMR (D2O, 282 MHz) −200 (m, 1F); MS (ESI) m/z 451 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH:7]1[O:14][CH:6]21)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C@@H:7]([OH:14])[C@@H:6]2[N:15]=[N+:16]=[N-:17])#[N:2]
Reactant: CC1(C)c2ccc(C#N)cc2C2OC21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)c2ccc(C#N)cc2[C@@H](N=[N+]=[N-])[C@@H]1O
Temperature: 60 °C
Yield: 56.3 %

Procedure:
A mixture of 5-cyano-1,1-dimethyl-2,3-epoxyindane (1.34 g), sodium azide (0.533 g), and ammonium chloride (0.44 g) in dry N,N-dimethylformamide (20 ml) was stirred and heated at 60° C., under nitrogen, for 3 h. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and then dried (Na2SO4). Removal of solvents in vacuo, followed by chromatography of the residue (Si gel, eluted with 30% EtOAc in pentane) gave the title compound as a gum (0.93 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9](I)[C:8](=[O:13])[NH:7][C:6]1=[O:14].[F:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[OH-].[K+].O>CC(C)=O>[F:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[C:9]1[C:8](=[O:13])[NH:7][C:6](=[O:14])[N:5]([CH2:4][C:3]2[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:2]=2[F:1])[C:10]=1[CH3:11]
Reactant: Cc1c(I)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: COc1cccc(B(O)O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)[nH]c2=O)c1F
Temperature: 15 °C
Yield: 83.3 %

Procedure:
To a reactor was charged 1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione 1b (20.0 kg), 2-fluoro-3-methoxyphenylboronic acid (8.7 kg), and acetone (60 L). The mixture was agitated and cooled to 15° C. and a potassium hydroxide/water solution (10.8 kg/64 L) was charged. The reactor contents were degassed for 30 min, then tri-t-butylphosphonium tetrafluoroborate (142 g) was added to the reactor and the contents mixed at 45° C. for 20 min. Palladium (II) acetate (52 g) was charged to the reactor and the contents were mixed at 55° C. The reaction mixture was stirred until the reaction was complete. Acetic acid (5.6 kg) was charged to the reactor over 1 hr, then the mixture was stirred at 55° C. for 30 min. The reactor contents were cooled to 25° C. over 2 hr. The solid was collected by centrifugation and the cake washed with water (40 L) followed by methanol (80 L). The solid was dried in a vacuum oven at 50° C. until the loss-on-drying was less than 1% to provide 5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1c (16.6 kg, 83% molar yield) as an off-white solid. LCMS (ESI) m/z 427.1 (MH+).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:26][N:25]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)C)(C)(C)C>C(O)=O>[CH2:29]([C:27]1[O:26][N:25]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:9]3([NH:7][CH3:6])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)(=[O:17])=[O:16])=[CH:19][CH:20]=2)[N:28]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCc1nc(-c2ccc(S(=O)(=O)C3(N(C)C(=O)OC(C)(C)C)CCNCC3)cc2)no1
Solvent: O=CO
Product: CCCCCCCCc1nc(-c2ccc(S(=O)(=O)C3(NC)CCNCC3)cc2)no1

Procedure:
A solution of (4-{[4-(5-octyl-1,2,4-oxadiazol-3-yl)phenyl]sulfonyl}-4-piperidinyl)-methylcarbamic acid t-butyl ester in formic acid was stirred at ambient temperature for 4 hours. Concentrated in vacuo to give 0.21 g of the product as a formate salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.C1COCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)Nc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 2-amino-5-nitropyridine (4.17 g, 30 mmol) in pyridine (30 mL) is stirred at rt and a solution of phenylacetyl chloride (4.64 g, 30 mmol) in THF (30 mL) is added dropwise. The mixture is stirred for 24 h and then poured into ice-water (250 mL) to afford a brown solid, which is used without further purification.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:30][C:31]1[N:36]=[C:35]([C:37]#[C:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:34]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[N:2]([CH3:1])[CH:3]([CH3:7])[C:4]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])=[C:35]([C:37]#[C:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:36]=1)=[O:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (34 mg, 0.17 mmol) and N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol) in DCM (1 ml) is stirred at RT for 20 minutes. This mixture is added to N-[6-amino-2-(2-phenylethynyl)pyridin-3-yl]oxane-4-carboxamide D5b (28 mg, 0.09 mmol) and DIPEA (17 μl; 0.10 mmol) in DCM (1 ml). After stirring for 6 days at 40° C. the reaction mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 to and concentrated in vacuo. The crude product (70 mg) is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[C:14]([NH:22][OH:23])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15].Cl>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:22]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[O-:23])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CC(C)(C)CC(C)(C)NO
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: CO
Product: CCOc1cc(C=[N+]([O-])C(C)(C)CC(C)(C)C)ccc1OC
Yield: 60 %

Procedure:
A solution of 3-ethoxy-4methoxybenzaldehyde, N-tert-octylhydroxylamine and catalytic amount of HCl in methanol was refluxed for 90 hrs with molecular sieves in a soxhlet for waster removal. The title compound was obtained in 60.0% yield as white powder, m.p. 77.5° C. (Rf=0.40 on a silica gel plate using hexanes:EtOAc, 3:2, v:v, as an eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:18])(=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].[ClH:19]>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:19])=[O:7])=[CH:4][C:3]=1[S:11](=[O:18])(=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14]
Reactant: Cl
Reactant: CCN(CC)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Solvent: O=S(Cl)Cl
Product: CCN(CC)S(=O)(=O)c1cc(C(=O)Cl)ccc1Cl

Procedure:
39 g of 4-chloro-3-diethylsulfamoylbenzoic acid were boiled under reflux in 200 ml of thionyl chloride until the development of HCl had finished and the thionyl chloride was then distilled off under reduced pressure. 4-chloro-3-diethylsulfamoylbenzoyl chloride was obtained as fair yellow oil.