Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1.O>C(Cl)(Cl)Cl.CCCCCC>[CH:28]1([C:31]([N:10]2[CH2:11][CH2:12][C@@H:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CC1
Reactant: Fc1ccc(O[C@@H]2CCNC[C@H]2c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=C(C1CC1)N1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1

Procedure:
To a mixture of 5.42 g of trans-4-(4-fluorophenoxy)-3-phenylpiperidine, 3.06 ml of triethylamine and 150 ml of chloroform is added, dropwise at room temperature under nitrogen, a solution of 2.0 ml of cyclopropylcarbonyl chloride in 100 ml of chloroform over a 20 minute period. A cold water bath is used to keep the temperature below 30° C. during the addition. After 105 minutes the reaction mixture is treated with 150 ml of water. After several minutes of vigorous stirring, the phases are separated and the chloroform phase is washed with 2 N hydrochloric acid (100 ml), saturated sodium chloride solution (150 ml), dried overnight over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which solidifies upon trituration with hexane. Recrystallization from 75 ml of boiling cyclohexane affords product as nearly colorless crystals, mp 113°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=2)[N:20]=1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]([F:25])([F:27])[F:26])=[N:22][N:23]=4)[N:20]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Brc1ccc(N2CCNCC2)nc1
Solvent: CCO
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(Br)cn4)CC3)nn12
Temperature: 80 °C
Reaction time: 20 h
Yield: 73.4 %

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine in ethanol (7 mL) was stirred at 80° C. for 20 hours. The reaction mixture was concentrated and partitioned between dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The aqueous phase was extracted twice with dichloromethane (2×50 mL). The organic phases were combined, washed with water (100 mL), and concentrated to give a residue that was purified by flash chromatography on silica-gel using ethyl acetate as eluant to give 6-[4-(5-bromopyridin-2-yl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine 0.353 g, 73.4%)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 87A, 7.77 g, 25.3 mmol) in methanol (50 mL) was treated slowly with concentrated sulfuric acid (0.01 mL). The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (75 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (4×50 mL). The organic layer was then dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid methyl ester (8.48 g, 87.5%) as yellow oil: EI-HRMS m/e calcd for C16H18F4O2 (M+) 318.1243, found 318.1240.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:24]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)c3ccc(F)cc3)c2)cc1Cl
Yield: 40 %

Procedure:
According to general General Sulfonylation Procedure 2 in example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added 4-fluoro-benzenesulfonyl chloride (18.6 mg, 96 μmol, 1.1 eq). The product was purified by precipitation in methanol and lyophilized to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-fluoro-benzenesulfonamide (13.5 mg, >95% purity, yield: 40%).
Reaction SMILES: [CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1.C(N(CC)CC)C.[C:61](Cl)(=[O:63])[CH3:62]>ClCCl>[C:61]([N:51]1[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][N:2]([CH3:1])[C:3](=[O:45])[C:4]2[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:12][C:11]=3[C:22]3[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=4)[CH:25]=[CH:24][N:23]=3)=[O:8])[CH:5]=2)[CH2:49][CH2:50]1)(=[O:63])[CH3:62]
Reactant: CC(=O)Cl
Reactant: CN(CCN1CCNCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 0 °C
Yield: 34.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N1-methyl-N1-(2-(piperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)-isophthalamide (150 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (3 mL), and triethylamine (63 mg, 0.62 mmol, 3.00 equiv). This was followed by dropwise addition of acetyl chloride (25 mg, 0.32 mmol, 1.50 equiv) with stirring at 0° C. The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of sodium bicarbonate and 2×5 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (130 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 56.5 mg (38%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.96 (d, J=5.1 Hz, 1H), 8.70 (d, J=9.0 Hz, 1H), 8.43 (s, 1H), 8.16-8.08 (m, 3H), 7.87˜7.86 (m, 1H), 7.79˜7.56 (m, 7H), 4.71 (s, 2H), 4.00-3.89 (m, 5H), 3.63-3.52 (m, 11H), 3.23 (s, 3H), 2.17 (s, 3H), 2.01 (s, 1H), 1.81 (d, J=4.8 Hz, 1H). MS (ES, m/z): 770 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:19][C:20]1[N:21]=[C:22]([NH:25][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:4][N:3]=2)[S:23][CH:24]=1
Reactant: COC(=O)c1ccccc1Oc1ccnc(Cl)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1Oc1ccnc(Nc2nc(C)cs2)c1

Procedure:
Using the method of Example 3, Step B, methyl 2-(2-chloropyridin-4-yloxy)benzoate (1.91 g, 7.23 mmol), 4-methylthiazol-2-amine (16.4 mL, 6.57 mmol), potassium phosphate (1.53 g, 7.23 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.105 g, 0.181 mmol) and Pd2(dba)3 (0.150 g, 0.164 mmol) were reacted in toluene (16 mL) and water (5 mL) to provide methyl 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoate as yellow solid. 1H NMR (CDCl3) δ 8.16 (d, 1H), 8.01 (dd, 1H), 7.57 (m, 1H), 7.35 (dt, 1H), 7.13 (d, 1H), 6.43 (dd, 1H), 6.29 (d, 1H), 6.21 (dc, 1H), 3.75 (s, 3H), 2.19 (d, 3H); Mass spectrum (esi) m/z=342 (100) (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:13])[O:6][C:7]([CH2:11]Br)=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2]>[N+]([O-])([O-])=O.[Ag+].C(O)C>[C:1]([C:4]1[C:5](=[O:13])[O:6][C:7]([CH:11]([O:6][CH2:5][CH3:4])[O:3][CH2:1][CH3:2])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(O)cc(CBr)oc1=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: CCOC(OCC)c1cc(O)c(C(C)=O)c(=O)o1

Procedure:
3-Acetyl-4-hydroxy-6-bromomethylpyran-2-one may be reacted with ethanol in the presence of silver nitrate to give 3-acetyl-6-diethoxymethyl-4-hydroxypyran-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[C:23]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=[CH:6][CH:7]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Reaction time: 20 h
Yield: 50.7 %

Procedure:
2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (100 mg, 0.34 mmol) was dissolved in 2 mL of dry pyridine under nitrogen. Then 4-acetamidobenzene-1-sulfonyl chloride (209 mg, 0.85 mmol) was added drop wise to the reaction mixture. The reaction mixture was allowed to stir for 20 h. Thin layer chromatography (petroleum ether:ethyl acetate=1:1, Rf=0.5) showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to afford 85 mg of 2-(3-(4-acetamidophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 51%. MS(ES+APCI) M+1=494.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[N:3]=1.O(C1C=C(C=CC=1)CO)C1C=CC=CC=1.[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+]>>[O:16]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCc2cccc(Oc3ccccc3)c2)n1
Agent: O=C([O-])[O-]
Agent: OCc1cccc(Oc2ccccc2)c1
Agent: [K+]
Product: c1ccc(Oc2cccc(COc3cncc(N4CCNCC4)n3)c2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(3-phenoxybenzyl)oxy]pyrazine (1.99 g, 6.36 mmol; obtained according to the procedure of example 50, step 1, starting from 3-phenoxybenzyl alcohol), piperazine (1.94 g, 22.5 mmol) and K2CO3 (0.88 g, 6.4 mmol). The yield of the title compound was 1.58 g (69%) which was obtained as an oil. Purity 100% (HPLC). MS m/z 363 (M+H)+. HRMS m/z calcd for C21H22N4O2 (M)+ 362.1743, found 362.1739.
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[H-].[Na+].[C:17]([O:22][CH3:23])(=[O:21])[C:18]#[C:19][CH3:20]>C1C=CC=CC=1>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([O:10]/[C:19](/[CH3:20])=[CH:18]\[C:17]([O:22][CH3:23])=[O:21])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1
Reactant: CC#CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC1(C)CC(O/C(C)=C\C(=O)OC)C(C)C(C)(CC)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of 3.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidinol (Compound 1) in 30 ml of benzene was added, in small portions at room temperature, 0.72 g of 50% sodium hydride. The mixture was then stirred for 30 minutes at room temperature. A solution of 2.2 g of methyl tetrolate in 10 ml of benzene was then added dropwise, with ice-cooling, to the mixture and the whole mixture was stirred at room temperature for 64 hours. The mixture was then poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulphate. After removing the solvent, the residue was distilled under reduced pressure, giving 3.4 g of Compound 97 as a pale yellow oil (bp 109°-111° C./0.15 mmHg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH2:10][C:11](O)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:12][CH2:11][CH2:10][CH:2]1[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: O=C(O)CC1Cc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCC1Cc2ccccc2O1

Procedure:
The starting material is prepared as follows: The solution of 14.2 g of 2-(2,3-dihydrobenzofuran-2-yl)-acetic acid [Gazz. Chim. Ital. 93, 52 (1963)] in 100 ml of tetrahydrofuran is added dropwise to the suspension of 4.55 g of lithium aluminum hydride in 200 ml of tetrahydrofuran while stirring. The mixture is refluxed for 18 hours, then cooled in an ice-bath and decomposed by adding 4.5 ml of water, 4.5 ml 15% aqueous sodium hydroxide and 14.6 ml of water. It is filtered, evaporated and the residue taken up in ethyl acetate. The solution is washed with aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried, evaporated and the residue distilled in a kugelrohr at 140°/0.1 mmHg, to yield the 2-(2-hydroxyethyl)-2,3-dihydrobenzofuran.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30]([C:32]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CCO>[C:25]([O:29][C:30]([C:32]1([CH2:36][NH:37][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:33][CH2:34][CH2:35]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)C1(CN)CCC1
Reactant: COC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Sc4ccccc4)ccc3c2O)CCC1
Yield: 92.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (43 mg) and 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (48 mg) in EtOH (0.5 mL) was microwaved at 140° C. for 1 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (58 mg). LC MS ESI+: 490 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:31])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(C)ccc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a stirred solution of 6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.61 g, 1.8 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.40 g, 1.57 mmol) in DCM (3 mL). After stirring for 2 h at 0° C., the solution was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.57 g, 89%) as a yellow solid which was not purified further.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.O>CC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)OCO2
Yield: 75 %

Procedure:
To a solution of 26.9 g of 1,3-benzodioxole-5-sulfonamide in 100 ml of acetone was added 150 ml of a 1 N sodium hydroxide solution. A solution of 26.4 g of 4-chlorophenylisocyanate in 85 ml of acetone was added to the reaction mixture with stirring. After stirring at room temperature for 18 hours, the reaction mixture was filtered and 150 ml of 1 N hydrochloric acid were added to the filtrate, thereby providing a precipitate. One liter of water was added, and the solid was recovered by filtration to provide the desired title product in 75% yield.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)Cl.CO>O1CCCC1.C(Cl)Cl.CCOC(C)=O>[N:1]1([C:7]2[N:8]=[C:9]3[N:17]([C:31](=[O:32])[CH2:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]([C:18]([F:20])([F:21])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(Cl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Cc1ccccc1)N1c2nc(N3CCOCC3)cc(=O)n2CC[C@H]1C(F)(F)F
Yield: 2.9 %

Procedure:
The product is prepared according to the procedure described in Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium hydride and 152 mg of phenylacetyl chloride in 4 ml of tetrahydrofuran. After two successive purifications by silica chromatography (eluent: CH2Cl2/MeOH; gradient of 100/0 to 98/02 then CH2Cl2/EtOAc 95/05), 12 mg of (8S)-2-(morpholin-4-yl)-9-(phenylacetyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a colourless lacquer, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[F:16][C:17]([F:27])([F:26])[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.C(N(CC)CC)C.O1CCOCC1>O>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:17]([F:27])([F:16])[F:26])[CH2:20][CH2:21]1)([O-:14])=[O:13]
Reactant: NC1CCN(CC(F)(F)F)CC1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: NS(=O)(=O)c1ccc(NC2CCN(CC(F)(F)F)CC2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
4-chloro-3-nitrobenzenesulfonamide (1.300 g), 1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride (1.201 g), and triethylamine (2.30 mL) were added to 1,4-dioxane (50 mL) and water (5 mL) and heated at 90° C. for 16 hours. The solution was concentrated on vacuum and purified by flash column chromatography on silica gel with ethyl acetate increasing to 5% methanol in ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[C:13]([CH3:22])=[N:14][CH:15]=[C:16]([CH:21]=1)[C:17]([O:19]C)=[O:18])[CH:6]=2.O1CCCC1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[C:13]([CH3:22])=[N:14][CH:15]=[C:16]([CH:21]=1)[C:17]([OH:19])=[O:18])[CH:6]=2
Reactant: COC(=O)c1cnc(C)c(-c2ccc3cc(N)ncc3c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)O)cc1-c1ccc2cc(N)ncc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
To a mixture of methyl 5-(3-aminoisoquinolin-7-yl)-6-methylnicotinate (189 mg; 0.6444 mmol) and tetrahydrofuran (4.0 mL; 49 mmol) was added lithium hydroxide (2.0 mL; 2.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified with 10% aqueous citric acid (2 mL), and the resulting yellow precipitate recovered via filtration, washed with water and tetrahydrofuran, and dried under vacuum to yield 114.6 mg of the title compound, which was carried forward without purification. LCMS (ESI): M+H=280.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH2:9][C:10]2[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=2)=[N:3]1.[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH:9]([C:10]2[N:11]=[C:12]([O:18][CH3:19])[CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[Br:25])=[N:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(OC)nc(Cc2ccccc2C2=NC(C)(C)CO2)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(OC)nc(C(Br)c2ccccc2C2=NC(C)(C)CO2)n1
Temperature: 75 °C

Procedure:
0.55 g of 2-(2-(4,4-dimethyl-oxazolin-2-yl)-benzyl)-4,6-dimethoxypyrimidine, 0.30 g of a N-bromosuccinimide, 0.03 g of benzoyl peroxide are dissolved in 60 ml of CCl4 and heated under reflux overnight at 75° C. The reaction mixture is filtered and the filtrate washed with 5% NaHCO3 solution (50 ml), 50 ml of water and the organic phase separated and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N1C=CC=CC=1>O>[C:19]1([NH:18][C:16](=[O:17])[NH:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:25](=[O:27])[CH3:26])[CH:3]=3)=[CH:14][CH:13]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Oc2ccc(NC(=O)Nc3ccccc3)cc2)ncn1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3ccccc3)cc2)ncn1
Yield: 52 %

Procedure:
N-(4-(6-Aminopyrimidin-4-yloxy)phenyl)-N′-phenylurea (60.0 mg, 0.187 mmol) was heated and stirred in an acetic anhydride (1 ml)—pyridine (1 ml) mixed solvent at 60° C. for 18 hours. After returning the reaction solution to room temperature, it was poured into water and the precipitated crystals were filtered out, washed with water and methanol and blow-dried to obtain the title compound (35.0 mg, 0.096 mmol, 52%) as colorless crystals.