Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:16][CH:17]=2)([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.Cl.O1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:17]=2)([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(C)(CO)c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@](CO)(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29.3 %

Procedure:
To a mixture of tert-butyl 4-(5-(2-(4-fluorophenyl)-1-hydroxypropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate (450 mg, 1.08 mmol) in DCM (20 mL) was added 4 M HCl/1,4-dioxane (3 mL). After stirred at RT for 15 h, the reaction mixture was concentrated, the residue was diluted by aq. NaHCO3 (20 mL) and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was separated by chiral Prep-HPLC to give (R)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol (100 mg, 29%) as a white solid. MS (ES+) C17H21FN4O requires: 316. found: 317 [M+H]+. Chiral HPLC, Column: IC 4.6*150 mm 5 um, Co-Solvent: EtOH:Hexane=1:1 (0.1% DEA), RT=4.22 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:15]1=2)=O)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].B.O1CCCC1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:3]([CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:15]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])[CH3:2]
Reactant: CCN(CC(=O)N1CCSc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CCN1CCSc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred solution of tert-butyl ethyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-oxoethyl)carbamate (1.01 g, 2.65 mmol) in tetrahydrofuran (5 mL) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran; 7.94 mL, 7.94 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then quenched via the slow dropwise addition (to avoid excessive bubbling) of MeOH (5 mL). The quenched reaction was then diluted with ethyl acetate and washed with water (2×) and saturated sodium carbonate (2×). The organic phase was dried, filtered, and concentrated, giving a red-orange oil (925 mg, 95%). 1H NMR (DMSO-d6) δ 7.59-7.41 (m, 1H), 7.39-7.32 (m, 1H), 7.24-7.13 (m, 1H), 3.69-3.62 (m, 2H), 3.58-3.48 (m, 2H), 3.45-3.35 (m, 2H), 3.28-3.16 (m, 2H), 3.15-3.08 (m, 2H), 1.32, 1.24 (2s, 9H), 1.04 (t, J=6.9 Hz, 3H); ESI-MS (m/z, %): 390 (M+Na, 70), 368 (MH+, 12), 312 (47), 268 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(C=O)cc2)C1)c1cc(F)cc(F)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(CN3CCCC3)cc2)C1)c1cc(F)cc(F)c1
Reaction time: 20 h
Yield: 51.1 %

Procedure:
0.75 g of (RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine and then 0.68 g of sodium triacetoxyborohydride are added to a solution of 0.10 g of pyrrolidine in 20 cm3 of 1,2-dichloroethane. After 20 hours at room temperature, 2 cm3 of 1 N sodium hydroxide are added, the product is extracted with 100 cm3 of dichloromethane, the organic phase is washed twice with 50 cm3 of water and then 50 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 13 cm), at an argon pressure of 0.5 bar with acetate as eluent and collecting 20 cm3 fractions. Fractions 10 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.39 g of (RS)-1-{(4-chlorophenyl)-[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 1.65 (4H, m, 2CH2), 2.40 (4H,m, 2NCH2), 3.02 (3H,s, SCH3), 3.50 (2H, s, NCH2Ph), 3.85 (2H, s, NCH2), 4.20 (2H, S, NCH2), 4.75 (1H, s, NCH), between 7.15 and 7.40 (9H, m, 9CH arom.), 7.48 (2H, d, J=7 Hz, 2CH arom.)].
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[C:17]([CH2:18][C:10]=3[C:9]([C:19]([O:21]CC)=[O:20])=[N:8]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>C(O)C>[C:1]1([N:7]2[C:11]3[C:12]4[C:17]([CH2:18][C:10]=3[C:9]([C:19]([OH:21])=[O:20])=[N:8]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Temperature: 0 °C
Yield: 91.8 %

Procedure:
1,4-Dihydro-1-phenyl-indeno[1,2-c]pyrazole-3-carboxylic acid, ethyl ester (3 g), prepared according to Example 1, is heated with 1% KOH solution in ethanol (100 ml) at reflux temperature for 20 minutes. The reaction mixture is diluted with ice water and acidified to pH 3 with 37% HCl. The precipitate is filtered, washed with water until neutral and dried in vacuo to give 1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazole-3-carboxylic acid (2.5 g) which is reacted with thionyl chloride (1.2 ml) in dioxane (60 ml) at the reflux temperature for 2 hours. After cooling the reaction mixture is evaporated to dryness in vacuo to give 1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazole-3-carbonyl chloride as crystalline residue. The crude product is dissolved in anhydrous dioxane (30 ml) and reacted for 2 hours under stirring at room temperature with the carbanion obtained by treatment of 2-cyano-acetanilide (1.6 g) with 50% sodium hydride (0.5 g) in anhydrous dimethylformamide/dioxane (1:1 (10 ml) at room temperature. The reaction mixture is then diluted with ice water and acidified to pH 2 with HCl. The precipitate is filtered and washed with water until neutral. Crystallization from dichloromethane/methanol gives 1.6 g of 2-cyano-3-(1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 273°-277° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]4[CH2:19][CH2:18][O:17][C:16](=[O:20])[C:12]4=[N:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[OH-:23].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3=[CH:14][N:13]=[C:12]([C:16]([OH:17])=[O:20])[C:11]([CH2:19][CH2:18][OH:23])=[C:10]3[CH:9]=[CH:8]2)=[CH:21][CH:22]=1
Reactant: O=C1OCCc2c1ncc1c2ccn1Cc1ccc(F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCO
Temperature: 60 °C
Yield: 94.6 %

Procedure:
To 7-(4-fluorobenzyl)-1,7-dihydropyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(2H)-one (0.11 g, 0.37 mmol) in methanol (10 mL) was added sodium hydroxide (0.066 g, 1.65 mmol) in water (2.0 mL). The reaction was heated to 60° C. for 3 hours. After cooling down, the reaction mixture was neutralized with 4N hydrochloric acid (0.42 mL, 1.65 mmol). It was concentrated and dried in vacuo to provide the crude title compound as a white powder (0.11 g, 94%). 1H NMR (DMSO-d6) δ; 8.93 (d, 1H, J=1.9 Hz), 8.06 (s, 1H), 7.36 (m, 2H), 7.16 (t, 2H, J=6.6 Hz), 6.96 (s, 1H), 5.63 (s, 2H), 3.66 (t, 2H, J=6.8 Hz), 3.44 (t, 2H, J=6.8 Hz). LCMS (APCl, M+H+): 315.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:32])(=[N:27][C:28](=[O:31])[NH:29][CH3:30])=[O:26])=[CH:21][CH:20]=1>>[CH3:30][NH:29][C:28]([N:27]=[S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:20][CH:21]=1)([CH3:32])=[O:26])=[O:31]
Reactant: CNC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CNC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Yield: 23.5 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (164.5 mg, 0.61 mmol) with (RS)—S-(4-aminophenyl)-N-(methylcarbamoyl)-S-methylsulphoximide (126 mg, 0.55 mmol) according to procedure 5c, the desired product is obtained in 23.5% yield (60 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CC(C)=O>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([CH3:31])=[C:10]3[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1,3-dibenzyl-2-methyl-1H-indol-5-yl)-phenol (0.155 g, 0.384 mmol) was reacted with K2CO3 (0.069 g, 0.499 mmol) and methyl bromoacetate (0.076 g, 0.499 mmol) in acetone (5 ml) to give the product (0.152 g, 0.320 mmol, 83%) as a viscous oil. 1H NMR (DMSO-d6) δ 2.35 (s, 3H), 3.70 (s, 3H), 4.10 (s, 2H), 4.80 (s, 2H), 5.42 (s, 2H), 6.94-7.00 (m, 4H), 7.09-7.13 (m, 1H), 7.20-7.30 (m, 8H), 7.39 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.9 Hz, 2H), 7.58 (d, J=1.7 Hz, 1H); [ESI(+)], m/z 476 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].[CH3:25]I>O1CCCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[C@H:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[C@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:25]
Reactant: CI
Reactant: COc1ccccc1CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1[C@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Reaction time: 0.75 h

Procedure:
19.1 g of sodium 1,1,1,3,3,3-hexamethyldisilazanate are added to a solution, cooled to −50° C., of 10 g of (4S,5S)-4-methyl-5-phenyl-3-[(2-methoxyphenyl)acetyl]oxazolidin-2-one in 150 cm3 of tetrahydrofuran, the mixture is stirred for 45 minutes at this temperature and then 7.72 cm3 of methyl iodide are added. The reaction mixture is then stirred for 15 hours at room temperature, then diluted with ethyl acetate, washed with 50 cm3 of water and then with 50 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized from isopropyl ether, filtered off and dried. There are obtained 4.2 g of (4S,5S)-4-methyl-5-phenyl-3-[(S)-2-(2-methoxyphenyl)propionyl]oxazolidin-2-one in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:24]3[CH:25]=[CH:26][N:22]([CH3:21])[N:23]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cn1ccc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1-methyl-1H-Pyrazole-3-carboxylic acid as starting materials, MS (LC/MS): 411.0 (M+H).
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:31](=[N:34]O)([NH2:33])[CH3:32]>ClCCl.N1C=CC=CC=1>[NH2:8][C@H:9]([C:13]1[O:15][N:34]=[C:31]([CH3:32])[N:33]=1)[CH:10]([CH3:11])[CH3:12]
Reactant: CC(N)=NO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1noc([C@@H](N)C(C)C)n1

Procedure:
A solution of BOC-L-valine (4.34 g, 20.0 mmol) in dichloromethane (20 mL) was cooled to 0° C. and treated dropwise with a solution of dicyclohexylcarbodiimide (2.06 g, 10.0 mmol) in dichloromethane (5 mL). After 1 hour the white solid which had formed was removed by filtration and the filtrate concentrated under reduced pressure. The residue was dissolved in pyridine (15 mL) and treated with acetamidoxime (488 mg, 6.6 mmol) in pyridine (5 mL) and the mixture heated at reflux for 1 hour. The pyridine was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed several times with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using 10% ethyl acetate in hexanes to elute the product (0.62 g, 25%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)Cl.CN([CH:31]=[O:32])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([CH:31]=[O:32])=[C:11]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc(N3CCOCC3)cc2=O)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2ncc(N3CCOCC3)c(C=O)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-methoxybenzyl)-5-(morpholin-4-yl)pyridazin-3(2H)-one (6.22 g, 20.60 mmol) in dry DMF (60 ml) was cooled to 5° C., then a solution of POCl3 (4.21 ml, 45.1 mmol) in dry DMF (12 ml) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. Then, the temperature was raised to 70° C. and stirring was continued for 80 min. After cooling, the volatile components were removed under reduced pressure and the residue was treated with crushed ice (70 g). The mixture was adjusted to pH 7-8 with aqueous NaOH. Then it was extracted with ethyl acetate (2×60 ml) and the combined extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was purified by crystallization from ethanol (95%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C:14]1[CH:15]=[N:16][C:17]([F:20])=[CH:18][CH:19]=1)=[O:4].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])=[C:7]([NH:13][C:14]2[CH:15]=[N:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:8]=1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Temperature: 100 °C
Yield: 94.1 %

Procedure:
A mixture of (S)-2-amino-N-[4-fluoro-2-(6-fluoropyridin-3-ylamino)phenyl]propionamide (193 mg, 0.66 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (165 mg, 0.69 mmol) and DIPEA (0.34 mL, 1.98 mmol) in n-butanol (1 mL) was heated at 100° C. in a sealed vial for 16 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a red solid (255 mg, 94%). LCMS (Method C): RT 2.40 min [M+H]+ 411.2.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Cl:8][C:9]1[CH:10]=[C:11](O)[CH:12]=[CH:13][CH:14]=1>>[C:1]([O:7][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:8])[CH:14]=1)(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC(=O)O
Reactant: Oc1cccc(Cl)c1
Product: C#CCCC(=O)Oc1cccc(Cl)c1
Yield: 95.1 %

Procedure:
According to the protocol described in Example 235(B), the reaction between pent-4-ynoic acid (590 mg, 6.0 mmol) and 3-chlorophenol (771 mg, 6.0 mmol) afforded 1.19 g of 3-chlorophenyl pent-4-ynoate (Yield: 95%) as colorless-oil.
Reaction SMILES: [Cl:1][CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:15][C:16]1[N:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=1>ClCCl>[CH3:23][C:18]1[CH:19]=[C:20]([CH3:22])[N:21]=[C:16]([NH:15][C:13]([NH:12][S:9]([CH:3]2[CH:2]([Cl:1])[CH:7]3[CH2:8][CH:4]2[CH2:5][CH2:6]3)(=[O:10])=[O:11])=[O:14])[N:17]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)C1C2CCC(C2)C1Cl
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)C2C3CCC(C3)C2Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
14.1 g (0.06 mole) of 3-chlorobicyclo[2.2.1]hept-2-ylsulfonyl isocyanate in 100 ml of dichloromethane were initially introduced and 7.4 g (0.06 mole) of 2-amino-4,6-dimethylpyrimidine were added in portions at 0° C. The mixture was initially stirred at 0° C. for 2 hours and then at room temperature for 18 hours and then worked up in analogy to Example 5. 14.1 g (66% of theory) of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-3-chlorobicyclo[2.2.1]hept-2-ylsulfonamide were obtained (viscous oil).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Yield: 91.5 %

Procedure:
A suspension of 0.5 g (2.9 mmol) of 6-chloro-3-nitro-2-picoline, of 0.73 ml (8.69 mmol) of pyrrolidine and of 0.8 g (5.79 mmol) of potassium carbonate is heated at 110° C. for 2 hours. The reaction mixture is subsequently concentrated under reduced pressure and then poured into 100 ml of water. A solid is recovered by filtration and is dried so as to obtain 0.55 g of the expected product in the form of a yellow solid which will be used as it is in the rest of the synthesis.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[Na+].Cl.[C:9]([NH2:13])(=[NH:12])[CH2:10][CH3:11].C(Cl)Cl>O>[CH3:5][O:4][C:2]([NH:13][C:9](=[NH:12])[CH2:10][CH3:11])=[O:3]
Reactant: COC(=O)Cl
Reactant: CCC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC(=N)NC(=O)OC
Yield: 91 %

Procedure:
298.6 parts of methyl chloroformate and 472.8 parts of 50% strength sodium hydroxide solution are added via two inlets to a mixture of 298 parts of propionamidine hydrochloride in 1,300 parts of methylene chloride and 200 parts of water, at from 20° to 25° C., in the course of 25 minutes, while stirring. The reaction mixture is stirred at 25° C. for three hours and diluted with 300 parts of water, and the phases are separated. The aqueous phase is extracted once with 200 parts of methyl chloride and the solvent is stripped off from the organic extract to give 325 parts (=91% of theory) of N-methoxycarbonylpropionamidine of melting point 87°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.C([NH2:15])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:8])[NH:15][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: NC=O
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Product: O=C1NC(=O)c2cc(Cl)ccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
The suspension of 4-chlorophthalic anhydride (3 g) in formamide (15 ml) was heated with stirring to 150° C. for 1 h. The resulting yellowish solution was cooled to rt and the product was fractionally precipitated by addition of water to yield 4-chlorophthalimide (1.91 g) as colourless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:26]([NH:30][CH2:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:34]([CH3:45])[CH:33]=1)[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH2:26]([N:30]([CH2:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:34]([CH3:45])[CH:33]=1)[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(-c2ncnc(Cl)c2C)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C
Temperature: 100 °C
Yield: 18.5 %

Procedure:
A mixture of 4-chloro-6-(4-methoxyphenyl)-5-methylpyrimidine (0.164 g, 0.7 mmol), diisopropylethylamine (0.24 mL, 1.4 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.29 g, 1.05 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature. The residue was dissolved in CH2Cl2 (50 mL), the organic solution was washed water (20 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting with 3:17–1:4 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (62 mg).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7]C(Cl)Cl.[CH2:11]([CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:12].Cl>ClCCl>[CH2:11]([CH:13]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[C:24]([CH:6]=[O:7])[CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:12]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(C=O)c1
Temperature: -20 °C
Yield: 97.5 %

Procedure:
Under an argon atmosphere, stirring and cooling at −20° C., titanium chloride (IV) (35.0 mL, 318 mmol) and dichloromethyl methyl ether (13.4 mL, 148 mmol) were added dropwise in sequence to a solution of ethyl 2-ethyl-3-(4-methoxyphenyl)propanoate (10.0 g, 42.3 mmol) in dichloromethane (500 mL). The mixture was stirred for 6 hours at −20° C. to −5° C. The reaction mixture was poured into a mixture of ice (600 g) with 3 mol/L hydrochloric acid (400 mL) and the dichloromethane layer was separated, which was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=4:1 v/v) to afford 10.9 g (97%) of the title compound as a light brown oily product.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6](=O)[NH:5][N:4]=1)[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[C:3]([CH2:1][CH3:2])=[N:4][N:5]=1
Reactant: CCc1n[nH]c(=O)c2cc(OC)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nnc(Cl)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-ethyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.