Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:47])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH:21]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH2:20][CH:19]2[C:40](=[O:46])[NH:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH:22]1[N:18]([C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:47])[NH:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:4]([OH:5])=[O:3])[CH:19]([C:40](=[O:46])[NH:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:20][CH:21]1[S:30]([C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3ccc(C)cc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)C2CC(C(=O)NCC(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)O)c3)C2c2ccccc2F)cc1
Yield: 6.3 %

Procedure:
A The process is performed as described in Example 1A, but starting with 3 g of (2RS,4SR,5RS)-1-{2-[3-(3-ethoxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-(4-methylphenyl)sulphonylpyrrolidine and 0.252 g of potassium hydroxide in a mixture of 80 cm3 of methanol and 20 cm3 of distilled water. After treatment, 0.18 g of (2RS,4SR,5RS)-3-(3-{2-[5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-(4-methylphenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid is obtained [Rf=0.6; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 393 K, δ in ppm): 0.96 (d, J=6.5 Hz, 6H: C(CH3)2); 1.85 (mt, 1H: CH); from 2.30 to 2.55 and 2.82 (2 mts, 1H each: CH2 at 3); 2.48 (s, 3H: CH3); 3.07 (mt, 2H: NCH2); from 3.60 to 3.80 and 3.88 (mt and d respectively, J=17 Hz), 1H each: COCH2N); 4.00 (mt, 1H: H4); 4.78 (t, J=7 Hz, 1H: H2); 5.71 (very broad s, 1H: H5); from 6.95 to 7.65 (mt, 6H: aromatic H); 7.49 (d, J=7.5 Hz, 2H: H of the aromatic at 4 (H ortho to the CH3)); 7.86 (d, J=7.5 Hz, 2H: H of the aromatic at 4 (H meta to the CH3)); 8.02 (mt, 1H: aromatic H (H2: ortho to the COOH)); 8.22 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6))].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:34])[CH:33]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:30]2[CH:29]=[C:28]([F:27])[CH:33]=[C:32]([F:34])[CH:31]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 3,5-difluorobenzeneboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([O:14]CC)(=O)[C:8]([O:10]CC)=O>C(OCC)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH3:6])[C:7](=[O:14])[C:8]1=[O:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CNCCNC
Solvent: CCOCC
Product: CN1CCN(C)C(=O)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a stirred solution of N,N′-dimethylethylenediamine (25.0 g, 0.28 mol) in 150 mL of dry diethyl ether was added diethyl oxalate (38.5 mL, 0.28 mol) in one portion. After a few minutes white crystals started to precipitate. The reaction mixture was stirred at room temperature overnight. The product was filtered and washed with dry diethyl ether. The product was dried under vacuum at 47° C. overnight to give colorless crystals (38.64 g, 96%). 1H NMR (200 MHz, CDCl3, δ): 3.50 (s, 4H), 2.99 (s, 6H). 13C{1H} NMR (200 MHz, CDCl3, δ): 157.35, 45.91, 34.74.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH3:12])[CH3:11].[Br:13]Br>OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Br:13][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([CH3:12])([CH3:11])[CH2:6]1
Reactant: BrBr
Reactant: CC1(C)CNc2ccc(F)cc21
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: CC1(C)CN(Br)c2ccc(F)cc21
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To a solution of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (1.6 g, 9.6 mmol) in 98% H2SO4 (20 mL), Ag2SO4 (1.6 g, 5.1 mmol) was added and the suspension was stirred under nitrogen for 30 minutes. The mixture was then cooled to −5° C., Br2 (508 μL, 9.9 mmol) was slowly added over 15 minutes and stirring maintained at the same temperature for 1 h. The reaction mixture was slowly poured over 200 mL of water/ice and subsequently filtered through Celite. 50% aqueous NaOH was added to the resulting solution (to pH ═9-10) and the product was extracted with EtOAc (3×). The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (1.58 g) as a dark oil. 1H NMR (DMSO-d6): 7.03 (1H, d), 6.64 (1H, d), 5.59 (1H, s), 3.20 (2H, s), 1.25-1.15 (6H, m). MS: [M+H]+=244.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:18](OC1C=CC(Cl)=C(Cl)C=1Cl)(=[O:23])[CH2:19][C:20]([O-])=[O:21]>C1(C)C=CC=CC=1>[OH:23][C:18]1[N:17]=[C:13]2[CH:12]=[C:11](/[CH:10]=[CH:9]/[C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:16]=[CH:15][N:14]2[C:20](=[O:21])[CH:19]=1
Reactant: O=C([O-])CC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Reactant: CC(C)c1csc(/C=C/c2ccnc(N)c2)n1
Solvent: Cc1ccccc1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Yield: 92.8 %

Procedure:
The 4-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-2-pyridinamine (2.65 g, 10.8 mmol) obtained in (D) was dissolved in toluene (100 ml), added with trichlorophenyl malonate (5.50 g, 11.9 mmol), and refluxed by heating for 1.5 hours. After the reaction mixture was concentrated, the deposited solid was collected by filtration and washed with n-hexane and ether to obtain the title compound (3.14 g, 93%) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CC(N(C)C)=O.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:8][C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1ncc(O)cn1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1ncc(Oc2ccnc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
A solution of 2-amino-5-hydroxypyrimidine (1.00 g, 9.00 mmol) in DMA (25 mL) was treated with potassium tert-butoxide (1.24 g, 11.05 mmol). The thick mixture was stirred at room temperature for 1 h. To this was added a solution of 2,4-dichloropyridine (1.21 g, 8.18 mmol) in DMA (10 mL) and the reaction was stirred at RT overnight under Ar. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The organic phase was separated and the aqueous was extracted with EtOAc (100 mL). The combined EtOAc layers were washed with 5% LiCl (100 mL) and brine (100 mL) and then dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine as a pale yellow solid (592 mg, 32%). MS (ESI) m/z: 223.0 (M+H+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][C:22]1[NH:23][C:24]2[CH:30]=[C:29]([C:31]3[CH:32]([CH3:38])[CH2:33][C:34](=[O:37])[NH:35][N:36]=3)[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][C:22]2[NH:23][C:24]3[CH:30]=[C:29]([C:31]4[CH:32]([CH3:38])[CH2:33][C:34](=[O:37])[NH:35][N:36]=4)[CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(CCN)[nH]c2c1
Product: CC(C)COCCc1ccc(OCC(O)CNCCc2nc3ccc(C4=NNC(=O)CC4C)cc3[nH]2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20][CH2:19]3)=[CH:14][CH:13]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH:27]([C:30]1[N:34]=[C:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:32][N:31]=1)([CH3:29])[CH3:28].ClCCl>>[CH3:24][C:21]1([CH3:25])[O:22][CH2:23][CH:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:6]3[N:5]=[CH:4][N:3]=[C:2]([N:38]4[CH2:37][CH2:36][CH:35]([C:33]5[O:32][N:31]=[C:30]([CH:27]([CH3:29])[CH3:28])[N:34]=5)[CH2:40][CH2:39]4)[C:7]=3[N+:8]([O-:10])=[O:9])=[CH:13][CH:14]=2)[CH2:19][O:20]1
Reactant: CC1(C)OCC(c2ccc(Oc3ncnc(Cl)c3[N+](=O)[O-])cc2)CO1
Reactant: CC(C)c1noc(C2CCNCC2)n1
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1noc(C2CCN(c3ncnc(Oc4ccc(C5COC(C)(C)OC5)cc4)c3[N+](=O)[O-])CC2)n1
Temperature: 27 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To an ice-cold solution of 4-chloro-6-(4-(2,2-dimethyl-1,3-dioxan-5-yl)phenoxy)-5-nitropyrimidine (500 mg, 0.0013 moles) and 3-isopropyl-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride (293 mg, 0.0015 mole) in dichloromethane (10 ml) diisopropyl ethyl amine (0.24 ml, 0.0016 mole) was added and the reaction mixture was stirred for 4 hours at 27° C. The reaction mixture was poured into ice cold water and extracted with dichloromethane. The organic extract was successively washed with water & brine, dried over calcium chloride and evaporated under reduced pressure. The crude product so obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to yield 450 mg product as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1)[NH2:5].[C:15](N1C=CC=CC1=O)([N:17]1C=CC=CC1=O)=[S:16].N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH2:17])=[S:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ncn(-c2ccc(N)cc2F)n1
Agent: N
Solvent: ClCCl
Product: Cc1ncn(-c2ccc(NC(N)=S)cc2F)n1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Step Q (2): Dichloromethane (125 mL) was added to a flask charged with 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (5.00 g, 26.0 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (6.65 g, 28.6 mmol). The crude reaction was concentrated in vacuo. Methanolic ammonia (2.0 M, 150 mL, 300 mmol) was added at rt to the dark-red solid residue. A light brown precipitate resulted. After stirring for 30 min, the crude reaction mixture was chilled in a −20 C freezer for 1 h. The solid precipitate was collected using vacuum filtration. The solid was rinsed with cold methanol and dried under high vacuum to afford 1-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (5.48 g, 84% yield) as an off-white solid. LC-MS (M+H)+ 252.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.02 (br. s., 1 H), 8.80 (d, J=2.1 Hz, 1 H), 7.91 (dd, J=13.4, 2.1 Hz, 1 H), 7.66 (t, J=8.7 Hz, 1 H), 7.33 (dd, J=8.4, 2.0 Hz, 1 H), 2.36 (s, 3 H).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)(=[O:6])=[O:7])[CH2:19][CH2:20]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
150 mg (0.434 mmol) of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (available from Lancaster) and 108 mg (0.434 mmol) of 4-butoxyphenylsulfonyl chloride (available from Matrix Scientific) were each dissolved in 10 mL of DCM and then combined. 1.5 eq. of DIEA (0.113 mL) was added to the mixture by syringe. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The resultant product 29 was purified through a column of silica gel with a gradient of 0% to 20% EtOAc in hexanes and the pure material was concentrated (yield 25%, white solid). 1H NMR (CDCl3): δ 8.058 (s, 1H), 8.003-7.983 (d, 1H), 7.851-7.831 (d, 1H), 7.688-7.641 (m, 3H), 7.017-6.980 (m, 2H), 4.055-4.022 (t, 2H), 3.843-3.746 (m, 3H), 2.286-2.226 (t, 2H), 2.068-1.901 (m, 3H), 1.843-1.773 (m, 2H), 1.6151-1.470 (m, 4H), 1.014-0.976 (t, 3H), 0.944-0.903 (m, 2H), 0.793-0.744 (m, 2H). LC: 100%. MS (e/z): 562 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:23][C:22](=[O:24])[O:21][N:20]=4)[C:8]=3[CH:25]=2)[CH2:3][CH2:2]1.Br[CH2:41][CH2:42][Cl:43].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:43][CH2:42][CH2:41][N:23]1[C:22](=[O:24])[O:21][N:20]=[C:19]1[C:9]1[C:8]2[CH:25]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([N:26]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]=2[O:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4noc(=O)[nH]4)c3cc2C2CC2)S(C)(=O)=O)cc1
Reactant: ClCCBr
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4noc(=O)n4CCCl)c3cc2C2CC2)S(C)(=O)=O)cc1
Temperature: 100 °C

Procedure:
A mixture of Example 8D (3.20 g, 5.82 mmol), 1-bromo-2-chloroethane (2.413 mL, 29.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.843 mL, 12.23 mmol) in N,N-dimethylformamide (30 mL) was heated at 100° C. for 2 hours. Additional 1-bromo-2-chloroethane (2.413 mL, 29.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.843 mL, 12.23 mmol) were added and the mixture was heated at 100° C. for another 1 hour. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed repeatedly with brine, dried with sodium sulfate, filtered and concentrated to give the title compound as a solid which was used without purification (3.55 g, quantitative yield).
Reaction SMILES: N[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13].N([O-])=[O:15].[Na+]>S(=O)(=O)(O)O>[OH:15][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13]
Reactant: O=N[O-]
Reactant: Cc1ccc2c(=O)[nH]ccc2c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc2c(=O)[nH]ccc2c1O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
5-Amino-6-methylisoquinolin-1(2H)-one (2.00 g, 11.48 mmol) was dissolved in sulfuric acid (24.3 mL, 287 mmol) (75%, 35 mL). The solution was cooled to 0° C. then a solution of sodium nitrite (12.1 mmol) in sulfuric acid (5 mL) was added dropwise over 15 min. The resulting solution was stirred at 0° C. for 45 min and then the reaction mixture was heated to 70° C. and stirred for 16 h. The reaction mixture was cooled in an ice bath for 15 min, then 100 g of ice was added. The mixture was filtered. The filter cake was washed with water for 4 times until the filtrate became neutral by pH paper. The filter cake was air dried to give 5-hydroxy-6-methylisoquinolin-1(2H)-one as a dark gray solid (1.39 g, 69% yield). MS (ESI, pos. ion) m/z: 176 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[C:29]#[N:30]>>[C:29]([C:28]1[CH:31]=[C:24]([CH:25]=[CH:26][C:27]=1[O:32][CH3:33])[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([OH:17])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:30]
Reactant: COc1ccc(CCl)cc1C#N
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Product: COc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C#N

Procedure:
From tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and 5-(chloromethyl)-2-methoxybenzonitrile, the title compound was prepared using a similar method to the one described in Example 1.16, Step A & B. LCMS m/z=377.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.28-2.37 (m, 1H), 2.68 (dd, J=16.4, 8.3 Hz, 1H), 2.87-2.98 (m, 2H), 3.73-3.81 (m, 1H), 3.94 (s, 3H), 3.99-4.06 (m, 1H), 4.11-4.18 (m, 1H), 5.02 (s, 2H), 6.13 (s, 1H), 6.85 (dd, J=8.7, 2.4 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 7.64 (dd, J=8.6, 2.1 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][S-:29].[Na+]>CN(C=O)C>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([S:29][CH3:28])[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Temperature: 1100 °C

Procedure:
To a solution 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (450 mg) in DMF (6 mL) was added sodium thiomethoxide (183 mg) and the reaction heated at 1100° C. for 16 h. After cooling to room temperature the reaction mixture was poured into ice water and the resulting precipitate filtered and air dried to give 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>C1COCC1>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[O:18]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a stirring solution of 5-amino-2-chlorobenzoic acid (1.74 g, 10.1 mmol) in anhydrous THF (60 mL), 3-(trifluoromethyl)benzoyl chloride (2.33 g, 11.2 mmol) was added slowly. The mixture was stirred at room temperature under argon for overnight. The solvent was removed under reduced pressure and re-crystallized from acetone/chloroform (v/v 1:1) to afford the title compound as a white solid (1.5 g, 43%).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[C:4](=[O:8])[CH2:5][NH:6][CH3:7])[CH3:2].[C:11]([NH:14][C:15]1[S:16][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][N:19]=1)(=[O:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([NH:14][C:15]1[S:16][C:17]([S:20]([N:6]([CH3:7])[CH2:5][C:4]([N:3]([CH2:9][CH3:10])[CH2:1][CH3:2])=[O:8])(=[O:21])=[O:22])=[CH:18][N:19]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Reactant: CCN(CC)C(=O)CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)CN(C)S(=O)(=O)c1cnc(NC(C)=O)s1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of N,N-diethyl-2-methylamino-acetamide (12 mmol), 2-acetylamino-thiazole-5-sulfonyl chloride (12 mmol) (prepared as described in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (15 mmol) in DCM (50 mL) was stirred at room temperature over night. The reaction mixture was diluted with DCM (50 mL) washed with 10% aq NaHSO4, water and brine, dried and concentrated to give 2-[(2-acetylamino-thiazole-5-sulfonyl)-methyl-amino]-N,N-diethylacetamide (59%) as pale yellow crystals. This was suspended in EtOH (10 mL) and added 8N HCl in dioxane (10 mL) and heated for 3H at 80° C. and then cooled to room temperature and concentrated in vacuo to give 2-[(2-amino-thiazole-5-sulfonyl)-methyl-amino]-N,N-diethyl-acetamide as a hydrochloride as colourless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12](Cl)=[O:13])=[C:5]2[N:4]=[N:3]1.Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].CN(C=O)C>N1C=CC=CC=1>[CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12]([NH:16][CH2:17][C:18](=[O:19])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:13])=[C:5]2[N:4]=[N:3]1
Reactant: Cn1nnc2c(C(=O)Cl)ncn2c1=O
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1nnc2c(C(=O)NCC(=O)c3ccccc3)ncn2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride (0.620 g; 2.90 mmol) and 2-aminoacetophenone hydrochloride (0.500 g; 2.90 mmol) was added DMF (6 mL) and pyridine (1.2 mL). The reaction mixture was stirred for 16 hours at room temperature, and then poured onto water. The precipitate was filtered, washed with water, and dried in the vacuum oven, and used without further purification. δH (DMSO-d6) 8.89 (1H, s), 8.68 (1H, t, J=5.6), 8.06 (2H, dd, J=8.3, 1.2), (1H, tt, J=7.4, 1.8), 7.58 (2H, m), 4.86 (1H, d, J=5.6), 3.89 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NCCCN1CCOCC1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCN2CCOCC2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
240 mg (0.900 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 156 mg (1.08 mmol) of N-(3-aminopropyl)morpholine were dissolved in 10 ml of DMF. 259 mg (1.35 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.