Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](O)(=O)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[NH4+]>>[CH3:11][C:12]1[NH:1][C:2]2=[N:3][C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[C:7]2[N:8]=1
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(N)c(N)n1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1cc(C)c2nc(C)[nH]c2n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2,3-Diamino-4,6-dimethylpyridine (25.0 g, 0.182 mol) was suspended in polyphosphoric acid (465 g), and acetic acid (31.3 mL, 0.547 mol) was added to the suspention, followed by stirring at 100° C. for 3 hours. The reaction mixture was moved to ice water and sodium carbonate (345 g) was added in a little portion while stirring. Then, 28% aqueous ammonium solution was added to the residue to control the pH to 9 and the mixture was stirred for 1 hour. Precipitated crystals were collected by filtration, and was washed with water, and the obtained crystals were dried under reduced pressure at 40° C. overnight to obtain Compound P11 (26.2 g, 0.162 mol, 89%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[C:29]4[N:30]=[C:31](S(C)(=O)=O)[N:32]=[CH:33][C:28]=4[C:27](=[O:38])[C:26]([C:39]([NH2:41])=[O:40])=[CH:25]3)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>>[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[C:29]4[N:30]=[C:31]([NH:14][C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)[CH:9]=5)[N:32]=[CH:33][C:28]=4[C:27](=[O:38])[C:26]([C:39]([NH2:41])=[O:40])=[CH:25]3)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ncc2c(=O)c(C(N)=O)cn(-c3ccc4c(c3)CCC4)c2n1
Reactant: Nc1cccc(CN2CCOCC2)c1
Product: NC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN4CCOCC4)c3)ncc2c1=O
Yield: 43.1 %

Procedure:
Using the procedure outlined in Example 23 (a and c), the title compound was prepared from 3-morpholin-4-ylmethyl-phenylamine (5 mg) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg). Purification by preparative HPLC (32 mL/min, 5-100% H2O/MeCN (0.01% TFA, v/v) gradient over 10 min) gave the title compound as a white solid (3.9 mg, 35%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.55 (br, 1H), 9.42 (s, 1H), 8.83 (s, 1H), 7.60 (br, 1H), 7.50 (br, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.13 (br, 2H), 6.23 (br, 1H), 4.00 (br, 4H), 3.32 (br, 2H), 3.08 (t, J=7.3 Hz, 2H), 3.00 (t, J=7.3 Hz, 2H), 2.72 (br, 2H), 2.23 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H28N6O3: 497.22 (M+H), Found: 497.1.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([O:23]C)=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>>[C:1]1([CH2:7][NH:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)NCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Product: CC(C)[C@H](NC(=O)NCc1ccccc1)C(=O)N[C@@H](C)C(=O)O

Procedure:
By the same procedure used to prepare the title compound of Example 1C, PhCH2NHCOValAlaOCH3 (671 mg, 2.00 mmole) and LiOH.OH (168 mg, 4.00 mmole) in 10% aqueous CH3OH (20 mL) gave after quenching with sulfonic acid ion exchange resin (18.0 g, 40 meq) 658 mg (100%) of pure product as an off-white flaky solid. Recyrstallization of a portion from ethyl acetate/CH3OH gave an analytical sample as very fine white crystals: mp 205°-206° C.; 1H NMR (DMSO-d6) δ 0.79 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 1.25 (d, J=7.3 Hz, 3H), 1.85-2.0 (m, 1H), 4.05-4.3 (m, 4H), 6.09 (d, J=9.3 Hz, 1H), 6.54 (t, J=6.0 Hz, 1H), 7.15-7.35 (m, 5H), 824 (d, J=7.0 Hz, 1H); MS (LSIMS) m/e 344 (22, M+ +Na), 322 (83, M+ +1), 233 (70), 205 (18), 189 (100); [α]D20 +15.3° (c=1.0, DMF); Analysis calculated for C16H23N3O4 : C, 59.79; H, 7.21; N, 13.08; found: C, 59.87; H, 7.30; N, 12.80.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([CH:19]2[O:21][CH2:20]2)=[CH:17][CH:16]=1.O>CS(C)=O>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][CH:19]([OH:21])[C:18]2[CH:22]=[CH:23][C:15]([CH3:14])=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Cc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a mixture of 65% sodium hydride (4.4 g, 0.12 mole) and dimethylsulfoxide (60 ml) was added dropwise a solution of 4-acetamidophenol (XV: R=CH3) (15.1 g, 0.1 mole) in dimethylsulfoxide (30 ml). After cooling the resulting mixture to 8° to 10° C., a solution of 4-methylstyrene oxide (XIX) (13.4 g, 0.1 mole) in dimethylsulfoxide (30 ml) was added dropwise thereto over 1 hour, followed by reaction at 15° C. for 4 hours. Water was added to the reaction solution, and the precipitated crystals were filtered and recrystallized from ethanol to obtain 17.5 g of β-(4-acetamidophenoxy)-α-(4-methylphenyl)ethyl alcohol (XIV: R=CH3) as white crystals (yield, 61.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[N:12][S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nnsc2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2nnsc2-c2ccc(N)cc2)cc1
Yield: 95 %

Procedure:
Thiadiazole 36 (11.8 g, 36.1 mmol) in EtOH (200 ml) was hydrogenated over 5% Pd/C (3.6 g) at 50 psi for 16 hours. The solution was filtered through a celite pad and washed with EtOH. The solvent was removed under reduced pressure, and the crude solid was recrystallized from EtOAc/MeOH to afford 32 (9.2 g, 95.1%), m.p. 236° C. (decomposes).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.N1C=CC=CC=1.[F:16][C:17]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>C(Cl)Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:25][C:17]=2[F:16])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Br)cc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
2-Fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) dissolved in DCM (10 ml), cooled to 0° C. and added oxalyl chloride (1.2 ml, 13.8 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoyl chloride quantitatively. 4-Bromo-2-fluoroaniline (1.4 g, 7.37 mmol) dissolved in DCM and added Pyridine (0.7 g, 8.84 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 2-fluoro-4-(methylsulfonyl)benzoyl chloride (2.08 g, 8.84 mmol). After continuing stifling at rt for 15 mins, reaction mixture diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (1 g) as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 460 (M+H).
Reaction SMILES: C(OC([NH:8][N:9]([C:21](=[CH:27][C:28]([O:30]CC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:12])=O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH2:10][N:9]2[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][C:28](=[O:30])[NH:8]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=C(C(=O)OCC)N(CC(=O)c1ccc(OC)cc1)NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)[nH]n1CC(=O)c1ccc(OC)cc1
Temperature: 85 °C
Yield: 91.1 %

Procedure:
A solution of crude diethyl 2-{2-(tert-butoxycarbonyl)-1-[2-(4-methoxyphenyl)-2-oxoethyl]hydrazinyl}but-2-enedioate (1.3 g) in toluene was added to polyphosphoric acid at 85° C. The reaction was heated at 85° C. for 1 hour after which time it was worked-up to give crude ethyl 2-[2-(4-methoxyphenyl)-2-oxoethyl]-5-oxo-2,5-dihydro-1H-pyrazole-3-carboxylate (800 mg). ESI-MI m/z [M+H]+ 305.3.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1CC(N2CCOCC2)CN1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CCOCC4)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4-(pyrrolidin-3-yl)morpholine via General Procedure E to give 26.9 mg of 287 following reverse phase purification. MS (Q1) 518.2 (M)+
Reaction SMILES: [C:1]([CH:3]1[CH2:9][CH2:8][S:5](=[O:7])(=[O:6])[CH2:4]1)#[N:2].[C-:10]#[N:11].[Na+:12]>>[C:1]([CH:3]([CH2:4][C:10]#[N:11])[CH2:9][CH2:8][S:5]([O-:7])=[O:6])#[N:2].[Na+:12]
Reactant: N#CC1CCS(=O)(=O)C1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCC(C#N)CCS(=O)[O-]

Procedure:
The following runs demonstrate the reaction of 3-cyanosulfolane with sodium cyanide to give sodium 3,4-dicyanobutane-1-sulfinate which was then either oxidized to sodium 3,4-dicyanobutane-1-sulfonate or converted by reaction with methyl iodide to the corresponding methylsulfone, i.e., 2-(2-methylsulfonylethyl)succinonitrile.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Cl:13][C:14]1[CH:15]=[C:16]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:37](=[O:43])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:17]=[CH:18][C:19]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69]O>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69][O:41][C:40](=[O:42])[CH2:39][CH2:38][C:37]([NH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:16]1[CH:17]=[CH:18][C:19]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[C:14]([Cl:13])[CH:15]=1)=[O:43]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Reactant: COCCOCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)CCC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Reaction time: 48 h

Procedure:
A solution of diethylazodicarboxylate (40% in toluene, 229 μL, 0.5 mmol) was slowly added to a mixture of N-(2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (200 mg, 0.46 mmol) (disclosed in WO 01/05746), triphenylphosphine (132 mg, 0.50 mmol), and 2-(2-methoxyethoxy)ethanol (55 mg, 0.46 mmol) in dry toluene (2.5 ml). The reaction mixture was stirred for 48 h and then poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[CH2:47][CH2:46][N:45]([CH3:48])[C:44]2=[O:49])=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[N:41][C:40]([CH:43]4[CH2:47][CH2:46][N:45]([CH3:48])[C:44]4=[O:49])=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CN1CCC(c2ccc(Br)cn2)C1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3CCN(C)C3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 57 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 3-(5-bromo-pyridin-2-yl)-1-methyl-pyrrolidin-2-one following a procedure analogous to that described in Example 1. Yield: 57% of theory; LC (method 1): tR=1.82 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][C@@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH3:3].[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH3:27])=[CH:24][C:23]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[CH:22][CH:21]=2>>[CH3:12][O:11][C:9](=[O:10])[C@@H:8]([O:7][C:6]1[CH:5]=[C:4]([CH:2]([N:19]2[C:20]3[C:25](=[CH:24][C:23]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[CH:22][CH:21]=3)[C:26]([CH3:27])=[C:18]2[CH3:17])[CH3:3])[CH:16]=[CH:15][CH:14]=1)[CH3:13]
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: COC(=O)[C@H](C)Oc1cccc(C(C)Br)c1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1cccc(O[C@@H](C)C(=O)OC)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 2, Example 1, using (2S)-methyl 2-(3-(1-bromoethyl)phenoxy)propanoate and allyl 2,3-dimethyl-1H-indole-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[S:13][C:14]=1[Cl:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:13][C:14]([Cl:15])=[C:10]([Br:9])[CH:11]=1)(=[O:18])=[O:17]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Product: Cc1noc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1Br
Yield: 25 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chloro-thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-bromo-5-chlorothiophene-2-sulphonyl chloride in 25% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 143°-145° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].C(S[C:13]1[N:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[C:17]=2[N:18]=1)CC>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:13]1[N:14]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:29][CH:30]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[C:17]=2[N:18]=1
Reactant: CCCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: OCC(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(OCC(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (0.052 ml) in N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 24 mg) at room temperature, and the mixture was stirred for 5 min. A solution of 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (535 mg) in N,N-dimethylformamide (3 ml) was added to the reaction mixture, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was allowed to be cooled to room temperature, saturated brine was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from a mixed solvent of ethyl acetate/hexane to give the title compound (8 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:26][CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:26]([N:18]([CH2:17][C:13]1[CH:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH:16]=[CH:15][CH:14]=1)[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CI
Reactant: CC(C)S(=O)(=O)NCc1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1cccc(-c2cccc(S(C)(=O)=O)c2)c1)S(=O)(=O)C(C)C

Procedure:
In analogy to example 10, step 3, propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide (example 49, step 2) was reacted with 1-iodo-2-methylpropane and cesium carbonate in N,N-dimethylacetamide to give propane-2-sulfonic acid isobutyl-(3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide as an off-white solid. MS: 441.3 ([M+NH4]+)
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15])([O-:3])=[O:2].I[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH:14]([C:5]2[CH:6]=[CH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]=2[N+:1]([O-:3])=[O:2])[OH:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(I)cc1
Reactant: O=Cc1ccc2ccccc2c1[N+](=O)[O-]
Product: COc1ccc(C(O)c2ccc3ccccc3c2[N+](=O)[O-])cc1

Procedure:
The titled compound was prepared from 1-nitro-2-naphthaldehyde and 4-iodoanisole in a procedure similar to that of example 1 (1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[C:18]([C:19]([OH:21])=[O:20])=[C:17]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35]N(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC.O>C(Cl)Cl.CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][N:9]1[C:18]([C:19]([O:21][CH3:35])=[O:20])=[C:17]([C:22]2[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1ccccn1
Reactant: COc1cc(-c2c(C(=O)O)n(NC(=O)OC(C)(C)C)c(=O)c3ccccc23)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 424.8 %

Procedure:
The compound obtained in Example 66 (1.0 g), dimethylaminopyridine (26 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (448 mg) are dissolved in a mixture of methylene chloride (20 ml) and methanol (340 ml). The mixture is stirred at room temperature for 10 minutes, and thereto are added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41 mg) and dimethylaminopyridine (26 mg), and the mixture is stirred at room temperature overnight. To the reaction mixture are added water and ethyl acetate, and the ethyl acetate layer is washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 2-(tert-butoxycarbonylamino)-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (438 mg) as listed in Table 6.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[OH:18])=[CH:10][CH:9]=[N:8]1>CCCCCC.C(O)(C)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])=[CH:10][CH:9]=[N:8]1
Reactant: COCCOCn1nccc1[C@H]1CCCC[C@@H]1O
Solvent: CC(C)O
Solvent: CCCCCC
Product: COCCOCn1nccc1[C@@H]1CCCC[C@H]1O

Procedure:
The (1S*,2R*)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol prepared in Example 158a was optically resolved with CHIRALFLASH IC (Daicel Corp.; hexane/isopropanol=1:1) to yield the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:20])[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][NH:7][N:6]=1)=[O:4]>[OH-].[Na+].CO>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:19])[C:12]=1[C:11]([NH:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][NH:7][CH:8]=1)=[O:20]
Reactant: COC(=O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.3 %

Procedure:
A mixture of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester (1.21 g) in 2 M aqueous NaOH/MeOH (1:1, 50 ml) was stirred at ambient temperature for 14 hours. Volatile materials were removed in vacuo, water (100 ml) added and the mixture taken to pH 5 using 1M aqueous HCl. The resultant precipitate was collected by filtration and dried through azeotrope with toluene to afford 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid as a beige solid (790 mg). (LC/MS: Rt 2.53, [M+H]+ 299.95).
Reaction SMILES: [CH3:1][CH2:2][C:3]([OH:5])=O.[Cl:6][S:7]([N:10]=C=O)(=[O:9])=[O:8]>C1C=CC=CC=1>[C:3]([NH:10][S:7]([Cl:6])(=[O:9])=[O:8])(=[O:5])[CH2:2][CH3:1]
Reactant: CCC(=O)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Product: CCC(=O)NS(=O)(=O)Cl
Yield: 99.6 %

Procedure:
n-Propionic acid (0.741 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound (1.71 g, quantitative) as a crystalline, hygroscopic solid.