Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]1([CH3:16])[CH2:6][C:5](=[O:7])[N:4](C(OC(C)(C)C)=O)[C@H:3]1[CH3:15]>C(OCC)(=O)C.Cl>[OH:1][C@:2]1([CH3:16])[C@H:3]([CH3:15])[NH:4][C:5](=[O:7])[CH2:6]1
Reactant: C[C@@H]1N(C(=O)OC(C)(C)C)C(=O)C[C@]1(C)O
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(=O)C[C@]1(C)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.9 %

Procedure:
tert-Butyl(2S,3S)-3-hydroxy-2,3-dimethyl-5-oxo-pyrrolidine-1-carboxylate (1.00 g) was dissolved in hydrogen chloride-ethyl acetate solution (10 mL, 4 mol/L), and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure, and recrystallized from isopropanol/n-hexane to give the title compound (309 mg, 55%) as colorless crystals. Furthermore, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate→methanol/ethyl acetate=1/10), and the obtained solid was crystallized from diisopropyl ether to give the title compound (220 mg, 39%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[Cl:19])=[O:8].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:22]([O:21][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][C:6]=1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[Cl:19])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)ccc1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Oc1ccc(Cl)cc1C(=O)Nc1ccc([N+](=O)[O-])cc1Cl)c1ccccc1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (1.27 g., 3.88 mmol) in pyridine (15 mL) was treated with 4-dimethylaminopyridine (30 mg) and benzoyl chloride (0.49 mL, 4.27 mmol) was introduced dropwise. The suspension was warmed to 50° C. for one hour then cooled to room temperature and stirred for 17 hours. The reaction mixture was partitioned between 1N aqueous HCl and ethyl acetate. The ethyl acetate phase was washed with water, then brine, dried over magnesium sulfate, and concentrated to an off-white solid. This was recrystallized from ethyl acetate/hexanes. 1HNMR (500 MHz, DMSO-d6): δ7.70 (M, 3H), 7.73 (m, 2H), 7.89 (m, 1H), 7.93 (M, 1H), 8.19 (m, 1H), 8.32 (m, 1H), 10.60 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]=2)[NH:16][CH:15]=1.[CH3:27]O>S(=O)(=O)(O)O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetic acid (1 g) in methanol (50 ml) containing sulphuric acid (2 drops) was boiled under reflux for 1.5 h under nitrogen. Removal of the solvent gave a solid (1.2 g). Part of this material (0.5 g) was purified by column chromatography (Whatman MFC silica, 25 g). Elution with ethyl acetate-light petroleum (1:1) gave the title compound as yellow crystals (0.4 g) m.p. 121°-124°.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@H:13](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C@H:11]2[CH2:26]Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:29][NH2:30]>CO>[C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@@H:13]3[CH2:12][C@H:11]2[CH2:26][N:30]3[CH3:29])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CCl)N(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C[C@@H]3C[C@H]2CN3C)cc1
Temperature: 90 °C
Yield: 76 %

Procedure:
A Parr bottle was charged with 3.8 g (8.56 mmol) of (2S, 4R)-1-(4-toluenesulfonyl)-2-(chloromethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine and 25 ml of methanol and the bottle was then tared. Methylamine gas was bubbled through the methanol solution until 2.65 g (85.6 mmol) of the gas had dissolved. The bottle was then sealed and heated to 90° C. After heating for 16 hours the reaction was cooled and the solvent was evaporated at reduced pressure. The residual solids were then partitioned between 50 ml of methylene chloride and 40 ml of 10% aqueous sodium hydroxide solution. The layers were separated and the organic layer was washed with 30 additional ml of 10% aqueous sodium hydroxide solution, and then dried over sodium sulfate. Evaporation of the solvent under reduced pressure provided 1.73 g of the desired product which represents a 76% yield. M.P.=87°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 91.4 %

Procedure:
A mixture of 3,5-dichlorophenylboronic acid (5 g, 26.2 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (5 g, 28.6 mmol), K2CO3 (7.24 g, 52.4 mmol) and Pd(PPh3)2Cl2 (368 mg) in THF (20 mL) and H2O (10 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether (50 mL) and H2O (50 mL). The aqueous layer was extracted with ether (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to afford 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (5.77 g; yield 85%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.42 (t, J=2.0 Hz, 2 H), 7.34 (d, J=2.0 Hz, 1 H), 6.05 (s, 1 H), 5.82 (s, 1 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[C:12](=S)=[S:13].C(N(CC)CC)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:12]([SH:13])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: NC(=NO)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Sc1nc(-c2ccc(Cl)cc2)no1
Temperature: 70 °C
Yield: 61 %

Procedure:
A mixture of p-chlorobenzamidoxime (170 parts), carbon disulphide (76 parts), triethylamine (101 parts) and pyridine (170 parts) was heated at 70° C. for three days. The solution was evaporated to dryness and the residue washed with 3-normal hydrochloric acid and recrystallised from benzene to give 3-(p-chlorophenyl)-5-mercapto-1,2,4-oxadiazole (130 parts, 61% yield), melting point 145°-147° C.
Reaction SMILES: [CH2:1]([CH2:8][NH:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:28][N:29]=2)=[CH:21][CH:20]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCCC1>[CH2:1]([CH2:8][NH:9][CH2:10][CH2:11][C:12]([CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:28][N:29]=2)=[CH:23][CH:24]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCNCCc1ccccc1
Reactant: CNCCc1ccc(C2=NCCN2C(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN=C1c1ccc(CCNCC(=O)CCNCCc2ccccc2)cc1

Procedure:
A solution of 2.08 g (9.06 mmol) of 3-(benzylmethylamino)propionic acid, 2.72 g (8.96 mmol) of tert.-butyl 2-[4-(2-methylaminoethyl)phenyl]-4,5-dihydroimidazole-1-carboxylate (see procedure 1 g), 5.05 ml (36.24 mmol) of triethylamine and 2.91 g (9.06 mmol) of TBTU in 350 ml of tetrahydrofuran was stirred at room temperature overnight. The mixture was then evaporated to dryness, and the residue was purified by column chromatography (mobile phase: dichloromethane/methanol/aqueous ammonia solution 9:1:0.1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[NH:9][C:10](=[O:11])[NH:8]2
Reactant: Nc1ncnc(Cl)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c2ncnc(Cl)c2[nH]1
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Combine 6-chloro-pyrimidine-4,5-diamine (7.46 mmol; 1.08 g); 1,1′-carbonyldiimidazole (2 equiv; 14.92 mmol; 2.42 g) and 1,4-dioxane (20 mL) and heat to reflux under nitrogen for 50 min. Evaporate the yellow solution to an oil. Add DCM (80 mL), let sit 1 h, filter and dry in vacuum oven at 45° C. to provide the title compound (1.22 g; 7.15 mmol; 96%) MS (ES+): m/z=169 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[Cl:12][CH2:13][C:14]#[C:15][CH2:16]O>>[Cl:12][CH2:13][C:14]#[C:15][CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: OCC#CCCl
Product: Fc1ccc2c(c1)c(I)nn2CC#CCCl
Yield: 58 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 4-chloro-2-butyn-1-ol in 58% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized.
Reaction SMILES: [C:1]1([P:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([OH:17])[CH3:16].N1C=CC=CC=1>CCOCC>[C:1]1([P:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:17][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOP(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of diphenylphosphinous chloride (135 mmol) in dry ether (120 mL) was treated dropwise at 5° C. with a solution of ethanol (200 mmol) and pyridine (134 mmol) in ether (120 mL). After addition was complete, the mixture was warmed to room temperature, filtered under argon, and the solid hydrochloride washed with ether. Evaporation of the solvent gave an oil which was purified by Kugelrohr distillation at 95° C. (0.1 mmHg). Yield: 119 mmol (88%); 1H NMR (CDCl3) δ 7.6-7.2 (m, 10 H), 3.95 (doublet of quartets, JH-H =7 Hz, JP-H =10 Hz, 2 H), 1.30 (t, J=7 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>C1COCC1>[F:31][C:32]([F:36])([F:35])[CH2:33][NH:34][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NCC(F)(F)F)nc2c1ccc(=O)n2-c1ccccc1F

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and trifluoroethylamine (200 mg, 2 mmol) were dissolved in THF (7 ml) and sealed in a vial under Ar. The mixture was heated in an oil bath to 600 for 4 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 60-90% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 187-188°, LC MS m/z=447(MH+) Retention time=2.27 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:25])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NCC1CCNCC1)c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of N-{[1-(tert-butoxycarbonyl)-4-piperidyl]methyl}pyridine-2-sulphonamide (1.45 g) in dichloromethane (10 ml) and the mixture stirred at ambient temperature for 1.5 hours. The solvent was removed under reduced pressure to yield crude N-(4-piperidyl methyl)pyridine-2-sulphonamide trifluoroacetate.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=2[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccc(Cl)cc1
Yield: 27.9 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 4-chlorophenylboronic acid (29 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a beige solid (15 mg, 0.034 mmol, 27%). LC-MS m/e 441.25 (M+H+)
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Br[CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:30])[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: CC(Br)c1ccccc1
Product: CC(c1ccccc1)n1c(=O)n(O)c(=O)c2sc3ccccc3c21

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with (1-Bromoethyl)-benzene and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.16 (d, J=7 Hz, 3H); 6.49 (q, J=7 Hz, 1H); 7.30-7.65 (m, 6H); 7.73 (dd, J=8 Hz, 1H); 8.10 (d, J=8 Hz, 1H); 8.31 (d, J=8 Hz, 1H); 10.80 (br s, 1H); Retention time=2.70 min., m/z=339.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:16]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:16]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2cccc(Cl)c2)CCC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chlorophenol (7.5 g, 58.0 mmol) in N,N-dimethylformamide (125 mL) was added cesium carbonate (28.3 g, 87 mmol) followed by the addition of ethyl 1-bromocyclobutanecarboxylate (9.8 mL, 58.0 mmol). The reaction mixture was stirred at 55° C. overnight. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (silica, heptane/ethyl acetate, 7:1) afforded ethyl 1-(3-chlorophenoxy)cyclobutanecarboxylate. MS (ESI+) m/z 255 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([O:11][C:12]1[C:17]([C:18]2[NH:19][C:20](=[O:34])[C:21]3[C:22](=[C:24]([CH2:32][CH3:33])[N:25]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:26]=3)[N:23]=2)=[CH:16][C:15](I)=[CH:14][N:13]=1)[CH2:8][CH2:9][CH3:10]>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:7]([O:11][C:12]1[C:17]([C:18]2[NH:19][C:20](=[O:34])[C:21]3[C:22](=[C:24]([CH2:32][CH3:33])[N:25]([CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[N:26]=3)[N:23]=2)=[CH:16][C:15]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:14][N:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1
Temperature: 60 °C
Yield: 93.2 %

Procedure:
Pd(PPh3)2Cl2 (11.2 mg, 0.016 mmol), trimethylsilylacetylene (179 μl, 1.29 mmol) and cuprous iodide (3 mg, 0.016 mmol) were added to a stirred slurry of 5-(2-butoxy-5-iodo-3-pyridinyl)-2-[2-(dimethylamino)ethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Example 44 in Annex 1, PCT Application, IB 00/01430) (330 mg, 0.647 mmol) in triethylamine (8 ml) and acetonitrile (2 ml) at room temperature under a nitrogen atmosphere. The mixture was heated at 60° C. for 3 h, cooled and extracted from brine with dichloromethane (2×100 ml). The organics were dried (MgSO4), filtered and concentrated to give a yellow solid. Purification by flash column chromatography (elution with DCM/MeOH, 95:5) gave the title compound as a pale brown oil (290 mg, 93%).
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][CH:11]([S:24](=[O:36])(=[O:35])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]1)[CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl.O>[NH2:13][CH2:12][CH:11]([S:24](=[O:36])(=[O:35])[NH:25][CH:26]1[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]1)[CH2:10][C:9]([OH:37])=[O:8]
Reactant: CC(C)N1CCC(NS(=O)(=O)C(CNC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)CC1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCC(NS(=O)(=O)C(CN)CC(=O)O)CC1
Temperature: 25 °C

Procedure:
24 mg (0.04 mmol) 4-Benzyloxycarbonylamino-3-(1-isopropyl-piperidin-4-ylsulfamoyl)-butyric acid benzyl ester were dissolved in 3 ml dichloromethane. At 0° C., 0.1 ml of a 1 M BBr3-solution in dichloromethane were added and the reaction mixture was allowed to warm to room temperature. After 24 h a few drops of water and 0.3 ml of a 1 M aqueous NaOH-solution were added. The mixture was concentrated under reduced pressure. The residue was taken up in DMF and filtered in order to get rid of salts. The filtrate was concentrated under vacuo to give crude 4-amino-3-(1-isopropyl-piperidin-4-ylsulfamoyl)-butyric acid, which was pure enough for further transformations. Yield: 14 mg
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([O:9][C:3]1[C:4](=[O:5])[CH:6]=[CH:7][O:8][C:2]=1[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1occc(=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1occc(=O)c1OCc1ccccc1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a 500 mL flask with 10.0 g (0.08 mol) of maltol (3-hydroxy-2-methyl-4H-pyran-4-one) in 120 mL of anhydrous DMF was added 14.1 mL (0.12 mol) of benzyl bromide and potassium carbonate (16.4 g, 0.12 mol) and heated at 80° C. overnight. After cooling to room temperature, the reaction was filtered and the solvents evaporated. The residual oil was brought up in 100 mL CH2Cl2 and washed twice with a saturated NaHCO3 solution, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. Product was purified on a silica gel column eluting with 0.5% MeOH in CH2Cl2 to yield a pale yellow solid in 75% yield (12.8 g, 59 mmol). 1H NMR (400 MHz, CDCl3) δ=7.59 (d, J=5.6 Hz, 1H), 7.36 (m, 5H), 6.36 (d, J=5.6 Hz, 1H), 5.15 (s, 2H, OCH2), 2.08 (s, 3H, CH3). ESI-MS(+): m/z 217.03 [M+H]+, 239.07 [M+Na]+.
Reaction SMILES: [CH2:1]1[CH:3]([C:4]([NH2:6])=[NH:5])[CH2:2]1.Cl.C(O[CH:11]=[CH:12][C:13]#[N:14])C>>[CH:3]([C:4]1[N:6]=[C:13]([NH2:14])[CH:12]=[CH:11][N:5]=1)([CH3:1])[CH3:2]
Reactant: CCOC=CC#N
Reactant: N=C(N)C1CC1
Agent: Cl
Product: CC(C)c1nccc(N)n1

Procedure:
This compound was made in analogy to example 2, step A] from cyclopropylcarbamidine hydrochloride (3 g) and 3-ethoxyacrylonitrile (2.5 mL) to give 2-isopropyl-pyrimidin-4-ylamine (1.36 g) as a light yellow foam. MS (ESI): 138.1 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.CN1CCOCC1.[CH3:41][S:42]([CH2:45][S:46](Cl)(=[O:48])=[O:47])(=[O:44])=[O:43].C(=O)([O-])O.[Na+]>ClCCl>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][S:46]([CH2:45][S:42]([CH3:41])(=[O:44])=[O:43])(=[O:48])=[O:47])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CS(=O)(=O)CS(=O)(=O)Cl
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)CS(=O)(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reaction time: 1 h

Procedure:
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (245 mg) and N-methylmorpholine (1.0 mL) were dissolved in dichloromethane (6.0 mL), (methylsulfonyl)methanesulfonyl chloride (0.40 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added under ice-cooling, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate to give the title compound (79.4 mg) as crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:32])[CH:24](Br)[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C)C=O.C(OCC)(=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH2:25][CH:24]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23]([O:22][CH3:21])=[O:32]
Reactant: COC(=O)CCC(Br)C(=O)OC
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCC(Oc1cccc2c1cc(C)n2Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture dimethyl-2-bromoglutarate (0.3 mL, 1.25 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 9 (0.49 g, 97%) as a white solid.