Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[OH:26])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([F:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=4[O:26][CH2:34]3)[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1F
Product: COc1cc2c(cc1F)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.43-7.22 (m, 10H), 7.16-7.09 (m, 1H), 7.06-6.92 (m, 3H), 6.60 (d, J=6.8 Hz, 1H), 6.54-6.48 (m, 1H), 6.37 (d, J=10.0 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 3.85 (s, 3H); MS (ES+) m/z 452.1 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18].Br.C1(NC2C=CC(N)=CC=2)C=CC=CC=1>C(#N)C>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:16]2[CH2:21][CH2:20][O:19][C:17]2=[O:18])=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C1OCCC1Br
Agent: Br
Solvent: CC#N
Product: O=C1OCCC1Nc1ccc(Nc2ccccc2)cc1

Procedure:
A mixture of 1.84 g (10 mmoles) of N1-phenyl-1,4-benzenediamine and 0.41 ml (5 mmoles) of α-bromo-γ-butyrolactone in 20 ml of acetonitrile is heated under reflux for 5 hours. After returning to 20° C., the precipitate which appears during the reaction (N1-phenyl-1,4-benzenediamine hydrobromide) is filtered and rinsed with 20 ml of acetonitrile. The filtrate is concentrated to dryness under vacuum and the residue is purified on a silica column (eluent: Heptane/AcOEt: 1/1 to 4/6). Beige powder. Melting point: 142.5-143° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1.C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>O>[OH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]2[C:25](=[O:26])[C:24]3[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]2=[O:31])[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
K2CO3 (19.4 g, 140.6 mmol) was added to a solution of trans-4-aminocyclohexanol hydrochloride (9.0 g, 59.35 mmol) in water (150 mL) followed by N-carbethoxy phthalimide (18.8 g, 85.96 mmol). A white precipitate was formed immediately. Stirring continued at RT for 1 h. The precipitate was filtered off, washed with water and dried to afford 12 g (84%) of 2-(4-hydroxy-cyclohexyl)-isoindole-1,3-dione.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][C@@H:17]2[CH3:29])[N:3]=1.Br.[CH3:31][C@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][C@@H:17]3[CH3:29])[N:3]=[C:2]([N:33]3[CH2:34][CH2:35][CH2:36][C@@H:32]3[CH3:31])[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: C[C@H]1CN(c2ncccc2Cl)CCN1c1cc(-c2ccc(F)c(Cl)c2)nc(Cl)n1
Reactant: C[C@H]1CCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CN(c2ncccc2Cl)CCN1c1cc(-c2ccc(F)c(Cl)c2)nc(N2CCC[C@@H]2C)n1

Procedure:
Dissolve 2-chloro-4-(3-chloro-4-fluorophenyl)-6-((S)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidine (45 mg, 0.1 mmol) and (S)-2-methylpyrrolidine hydrobromide (0.2 mmol, prepared essentially as described by Nijhuis et. al. (1989) J. Org. Chem. 54:209-216) in CH3CN; 2.0 mL) under nitrogen atmosphere. Add K2CO3 (55 mg, 0.4 mmol) and heat at 80° C. for 20 hours. Concentrate under vacuum, dilute with water (5.0 mL), extract with EtOAc (3×3 mL) and dry with MgSO4. Filter, and concentrate under vacuum to afford crude product. Purify by flash column chromatography using 10-20% EtOAc/hexane to afford the title product as viscous oil. NMR (CDCl3) δ1.31 (3H, d, J=2.1), 1.41(3H, d, J=2.3), 1.62 (2H, m), 1.93 (3H, m), 3.00 (2H, m), 3.35 (1H, t), 3.65 (2H, m), 3.81(2H, m), 4.35 (1H, m), 4.68 (1H, bs), 6.22 (1H, s), 6.87 (1H, m), 7.16 (1H, t), 7.61 (1H, m), 7.88 (1H, m), 8.06 (1H, m), 8.20 (1H, m). Mass spec m/z=501.22.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.CO/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].Br.C(O)(=O)C>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1
Reactant: CO/C=C/C(=O)OC
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 5 h
Yield: 8.9 %

Procedure:
1.27 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 1.16 g of methyl trans-3-methoxyacrylate and 12 mL of glacial acetic acid were mixed, then, 797 mg of 30 wt % hydrogen bromide/acetic acid solution was added dropwise into the mixture at an inner temperature of 25° C., the mixture was stirred for 5 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 0.15 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 8%.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24](O)=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(methylsulfonyl)-acetamide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)-benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (Example 4) following General Procedure L using methanesulfonic acid amide in place of the sulfamide.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].N1C=CN=C1.[C:12]([Si:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)Cl)([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[Si:16]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:12]([CH3:15])([CH3:14])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45 %

Procedure:
Commercially available 1,4-butanediol (400 g) was dissolved in DMF (120 ml), added with imidazole (3.02 g) and t-butyldiphenylchlorosilane (12.2 g), and stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and then added with a saturated aqueous ammonium chloride solution, followed by separation/extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (6.56 g) as a transparent and colorless oily substance.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:7])[CH3:6].[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>C1COCC1>[CH3:3][N:4]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([F:8])=[CH:10][CH:11]=1)[C:5](=[O:7])[CH3:6]
Reactant: Fc1ccc(CBr)cc1
Reactant: CNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
To a solution of NaH (6.86 g, 0.172 mole, 60% in mineral oil, 1.3 equiv) in THF (250 mL), add dropwise a solution of N-methylacetamide (11.6 g, 0.159 mole, 1.2 equiv) in THF (90 mL). After about 20 min, add 4-fluorobenzylbromide (25 g, 0.132 mole). Stir for about 62 hours then pour over ice water (300 mL) and extract with ethyl acetate (400 mL and 200 mL). Combine the organic layers and wash with water (300 mL), dry over Na2SO4, filter and concentrate to an oil. Dissolve the oil in acetonitrile and extract with hexane to remove the mineral oil to give 22.79 g N-methyl-N-(4-fluorobenzyl)acetamide: mp=48-54° C.; Rf=0.45 (4% MeOH/methylene chloride); 1H NMR (CDCl3) 7.27-6.93 (m, 4), 4.5 (d, 2), 2.91 (s, 3), 2.14 (s, 3).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.C[N:34]1[C:38](=O)[CH2:37][CH2:36][CH2:35]1>N1CCCC1>[F:27][C:26]([F:29])([F:28])[C@:25]([C:23]1[N:22]=[N:21][N:20]([CH2:19][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[CH:11][C:2]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=1)([OH:32])[CH2:30][CH3:31]
Reactant: CN1CCCC1=O
Reactant: CCC(O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Solvent: C1CCNC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(N4CCCC4)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (75 mg, 0.16 mmol) in NMP (0.5 mL) and pyrrolidine (0.5 mL) was stirred at 130° C. in a microwave for 20 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with NH4OH/ethanol/dichloromethane, 1:9:90) gave the title compound. MS (+ESI): 501 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:36]([CH3:35])(=[O:38])=[O:37])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCNS(C)(=O)=O

Procedure:
According to the procedure described in Example 4a) 103 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide was reacted with methanesulfonylchloride to give 105 mg 4-tert.-butyl-N-[6-(2-(methanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide. LC-MS: tR=5.12 min, [M+1]+=565.58, [M−1]−=563.69.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Methanesulfonyl chloride (966 μl, 12.5 mmol) was added dropwise to a solution of 1-benzylpiperazine (2 g, 11.3 mmol) and triethylamine (1.74 ml, 12.5 mmol) in dry methylene chloride (30 ml) cooled at 0° C. After stirring for 1 hour at ambient temperature, the mixture was partitioned between water and methylene chloride. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (7/3) to give 1-benzyl-4-methylsulfonylpiperazine (2.5 g, 87%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]([OH:32])=[O:31])[CH:28]=2)[CH:23]=[CH:22]1.Cl>ClCCl>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:31])[CH:28]=2)[CH:23]=[CH:22]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc2cc[nH]c2c1
Yield: 99 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5 g, 26.1 mmol) was added to a stirred solution of benzyl alcohol (2.47 ml, 23.9 mmol), 1H-indole-6-carboxylic acid (3.5 g, 21.7 mmol) and N,N-dimethylaminopyridine (3.4 g, 28.3 mmol) in dichloromethane (40 ml) at room temperature under a nitrogen atmosphere. After 12 h the reaction mixture was poured into 1M hydrochloric acid (200 ml) and extracted with dichloromethane (2×200 ml). The combined organics were dried (MgSO4) and concentrated to give a brown oil. Flash column chromatography (elution with dichloromethane) gave the subtitle compound (5.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:15][CH:14]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCc2ccc(Br)cc2)cc1
Yield: 73.1 %

Procedure:
Methyl 4-hydroxybenzoate (1.09 g, 7.14 mmol), 2-(4-bromophenyl)ethanol (1.44 g, 7.14 mmol), and triphenylphosphine (2.06 g, 7.86 mmol) were dissolved in THF (44 mL), and then diethyl azodicarboxylate (3.57 mL, 40% toluene solution, 7.86 mmol) was added thereto while stirring under ice-cooling. The mixture was further stirred at room temperature for 2 days, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 19:1 to 9:1, v/v) to give 1.75 g of the title compound (white powder, yield: 73%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([Cl:23])=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Solvent: ClCCl
Product: CNC(=O)c1sc(Cl)c(C)c1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
An ice-cold solution of 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (0.105 g, 0.33 mmol) in methylene chloride (4 mL) was treated with sulfuryl chloride (33 μL). The mixture was stirred for 16 hours and concentrated. Chromatography on preparative TLC plate (hexanes/ethyl acetate/methanol (50:25:1)) gave 5-chloro-3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (10.4 mg, 9%): 1H NMR (300 MHz, CDCl3) δ 9.9 (s, 1H), 8.33 (s, 1H), 5.82 (br, 1H), 3.05 (d, 3H), 2.22 (s, 3H); MS (m/e): 351.1 (M+1). 1770b) Following a procedure analogous to Example 1741e, 5-chloro-3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide and 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one were converted to 5-chloro-3-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide: 1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 8.07 (br, 1H), 7.37 (d, 1H), 7.2 (dd, 1H), 7.15 (br, 1H), 7.0 (d, 1H), 5.85 (q, 1H), 4.43 (t, 2H), 3.33 (s, 3H), 2.92 (d, 3H), 2.85 (t, 2H), 2.0 (s, 3H); MS (m/e): 507.2 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]#[N:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])C.O[Li].O>C1COCC1.O>[Br:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]#[N:18])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1CC#N
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#CCn1c(C(=O)O)cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
To a solution of 1.0 eq. of 5-Bromo-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (prepared according to U.S. Pat. No. 5,854,245) in a mixture of THF/H2O ((9/1) was added LiOH.H2O (1.0 eq.) and the reaction mixture stirred 6 h at RT, acidified to pH 2 and then partially concentrated until precipitation of the crude product which was filtered off and washed with Et2O and then dried to give the desired product as a beige solid (86%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8](=[O:15])[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[Br:18]Br>C(Cl)Cl>[Br:18][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=1)[C:8](=[O:15])[C:9]([CH3:13])([CH3:14])[CH2:10][CH2:11][Cl:12]
Reactant: BrBr
Reactant: CC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
136 g (0.5 mol) of 1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-pentan-2-one are dissolved in 1,000 ml of methylene chloride. 79.9 g (1 mol) of bromine are added dropwise, at room temperature, in such a manner that the solution is constantly decolourised. Thereafter, stirring is continued for 1 hour at room temperature, and the reaction mixture is concentrated by distilling off the solvent. 1-Bromo-1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-pentan-2-one is obtained quantitatively, that is to say 177 g, and is directly reacted further. ##STR31##
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](N)=[O:16])[C:6]2=[CH:5][CH:4]=1)[CH3:2].[OH2:26].[OH-].[K+].Cl>C(O)C>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][C:22]([CH3:25])([CH3:23])[CH3:24])[CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:16])=[O:26])[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: O
Reactant: CCc1ccc2c(-c3cccc(C(N)=O)c3)cc(CC(C)(C)C)nn12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc2c(-c3cccc(C(=O)O)c3)cc(CC(C)(C)C)nn12
Temperature: 60 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a solution of 3-(7-ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzamide (35 mg) in ethanol (1 mL) was added water (0.2 mL) and potassium hydroxide (68.9 mg) at ambient temperature. The reaction mixture was heated at 60° C. After 2 hours, potassium hydroxide (100 mg) was added. After 5 hours, potassium hydroxide (100 mg) was added. After 12 hours, the mixture was acidified with 1N hydrogen chloride. The precipitate was filtered, washed with water and ethyl acetate to give 3-(7-ethyl-2-neopentylpyrrolo-[1,2-b]pyridazin-4-yl)benzoic acid as an yellow solid (19 mg, 54.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](O)=[O:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1cncc(C#Cc2cccc(N)c2)c1
Product: COC(=O)c1cncc(C#Cc2cccc(NC(=O)c3ccc(F)c(Cl)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 5-((3-aminophenyl)ethynyl)nicotinate and 3-chloro-4-fluorobenzoic acid are converted to the title compound.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12](OC)=[O:13])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][NH2:20]>CO>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:19][NH2:20])=[O:13])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Solvent: CO
Product: NNC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Temperature: 65 °C
Yield: 71.1 %

Procedure:
Methyl 3-(pyrrolidin-1-ylsulfonyl)benzoate (150 mg, 0.557 mmol) was added to the hydrazine (35.7 mg, 1.114 mmol) in methanol and refluxed for 12 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography to yield 3-(pyrrolidin-1-ylsulfonyl)benzohydrazide (110 mg, 0.396 mmol, 71.1% yield). 1H NMR (CDCl3, 400 MHz): δ 8.18 (m, 1H), 8.03 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=8.0 Hz), 7.78 (bs, 1H), 7.63 (t, 1H, J=7.6 Hz), 4.17 (bs, 2H), 3.25 (m, 4H), 1.77 (m, 4H). Mass [M+H]+: 270.1
Reaction SMILES: [C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH2:13][CH3:14]>CO.[Pd]>[C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([F:12])=[CH:5][C:4]=1[CH2:13][CH3:14]
Reactant: CCc1cc(F)c([N+](=O)[O-])cc1OC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCc1cc(F)c(N)cc1OC(=O)OC
Reaction time: 8 h
Yield: 94 %

Procedure:
To a flask charged with 10% Pd/C (170 mg) under inert atmosphere was added a solution of 2-ethyl-4-fluoro-5-nitrophenyl methyl carbonate (1.7 g, 6.99 mmol) in methanol (17 mL). The mixture was stirred overnight under an atmosphere of H2. The reaction was filtered and concentrated in vacuo to provide 5-amino-2-ethyl-4-fluorophenyl methyl carbonate (1.400 g, 6.57 mmol). 1H NMR (400.0 MHz, DMSO-d6) δ 6.92 (d, J=12.0 Hz, 1H), 6.52 (d, J=8.1 Hz, 1H), 5.16 (s, 2H), 3.81 (s, 3H), 2.33 (q, J=7.5 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:25]>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(SCc2cccc(F)c2)cc1
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(SCc2cccc(F)c2)cc1
Yield: 47 %

Procedure:
Prepared in analogy to example 3 from N-[4-(3-fluoro-benzylsulfanyl)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=47%. Colorless solid. MS: m/e=319.3 (M++H).