Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][N:11]=3)[N:6]([C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=4)[CH2:14]3)[C:5]2=[O:26])[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:38]2C=C[CH:41]=[CH:42][C:37]=2[N:36]=N1.C(N(C(C)C)CC)(C)C.Cl.NC1(C#N)CC1>C(Cl)Cl>[C:38]([C:37]1([NH:36][C:23]([C:20]2[S:19][C:18]([NH:17][C@H:15]3[CH2:16][C@H:13]([N:6]4[C:7]5=[N:8][CH:9]=[CH:10][N:11]=[C:12]5[N:4]([CH:1]5[CH2:2][CH2:3]5)[C:5]4=[O:26])[CH2:14]3)=[N:22][CH:21]=2)=[O:24])[CH2:41][CH2:42]1)#[N:34]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1cnc(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)s1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC1(NC(=O)c2cnc(N[C@H]3C[C@H](n4c(=O)n(C5CC5)c5nccnc54)C3)s2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxylic acid, (EXAMPLE 149), (0.070 g, 0.188 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.147 g, 0.282 mmol), diisopropylethylamine (0.049 ml, 0.282 mmol), and 1-amino-1-cyclopropanecarbonitrile hydrochloride (0.033 g, 0.282 mmol) in DCM (5 mL) was stirred at room temperature for 12 hours. Purification of the reaction mixture using silica chromatography with ISCO eluting with 0-80% EtOAc/hexanes gave the title compound N-(1-cyanocyclopropyl)-2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxamide (0.060 g, 0.137 mmol, 73.1% yield). m/z: 437 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: ppm 8.78 (s, 1 H) 8.32 (d, J=6.65 Hz, 1 H) 7.93-8.05 (m, 2 H) 7.40 (s, 1 H) 5.18 (quin, J=8.51 Hz, 1 H) 4.31-4.53 (m, 1 H) 3.21-3.41 (m, 2 H) 2.88-3.05 (m, 1 H) 2.29-2.44 (m, 2 H) 1.44-1.60 (m, 2 H) 1.23-1.35 (m, 2 H) 0.93-1.10 (m, 4 H).
Reaction SMILES: [C:1](Cl)([NH:3][S:4](Cl)(=[O:6])=[O:5])=O.[CH:9]([NH2:12])([CH3:11])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:3][S:4]([NH:12][CH:9]([CH3:11])[CH3:10])(=[O:6])=[O:5]
Reactant: O=C(Cl)NS(=O)(=O)Cl
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)NC(C)C
Temperature: 20 °C
Reaction time: 3 h

Procedure:
38.9 parts by weight of methylamidosulfonyl chloride were added a little at a time to a mixture of 17.7 parts of isopropylamine, 33.3 parts of triethylamine and 120 parts of tetrahydrofuran (THF), which was kept at from -70° to -65° C. The mixture was stirred at 20° C. for 3 hours, the insoluble material was filtered off and the solution was evaporated to dryness. The residue on the filter was extracted by stirring with methylene chloride, the mixture was filtered and the solution was concentrated. 30.6 parts of N-methyl-N'-isopropylsulfamide of melting point 50°-52° C. (starting substance) were obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)=[O:8])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a solution of 3-formylbenzoic acid (600 mg, 3.99 mmol) in DCM (12 mL) were added tert-butyl piperazine-1-carboxylate (818.8 mg, 4.40 mmol), HATU (1.82 g, 4.80 mmol), NMM (1.1 mL, 9.99 mmol), and DMAP (49 mg, 0.39 mmol) at 0° C. Reaction was stirred at RT for 16 h. TLC analysis indicated complete consumption of starting material. The reaction mixture was diluted with DCM and washed with water. Organic layer was separated and dried over Na2SO4 and concentrated. Column chromatography of crude material afforded pure product tert-butyl 4-(3-formylbenzoyl)piperazine-1-carboxylate as off-white solid (990 mg, 78%).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:22]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[S:7][C:6]=2[C:18]=1[N+:19]([O-:21])=[O:20].N1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(OCC)(=O)C>[OH:22][C:3]1[C:2]([OH:1])=[C:18]([N+:19]([O-:21])=[O:20])[C:6]2[S:7][C:8]([C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C(=O)N3CCOCC3)sc2c([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(c1cc2cc(O)c(O)c([N+](=O)[O-])c2s1)N1CCOCC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
(6-Hydroxy-5-methoxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (1.0 g) was dissolved in ethyl acetate (11 ml) and pyridine (14 ml) added into. Next aluminum trichloride (0.47 g) was gradually added into the solution. The reaction mixture was refluxed for 2 hours at 110° C. To the warm reaction (60° C.) solution was added the mixture of ice and concentrated hydrochloric acid (1:1) and then it was stirred at room temperature for one hour. The solid was filtered, washed with water and treated with diethyl ether.
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]=[CH:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:35]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>>[C:12]([O:11][C:9]([NH:8][C@H:5]1[CH2:6][CH2:7][C@@H:2]([Cl:35])[CH:3]=[CH:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@H](O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a mixture of trans-1-hydroxy-4-(tert-butoxycarbonylamino)-2-cyclohexene (2.93 g, 13.8 mmol) in hexachloroacetone (70 mL) was added triphenylphosphine (7.51 g, 28.6 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the thus obtained oil was purified by column chromatography on silica gel (10:1 hexanes-ethyl acetate) and provided 1.98 g (62%) of cis-1-(tert-butoxycarbonylamino)-4-chloro-2-cyclohexene as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C@H:17](O)[CH2:18][C@@H:19]([OH:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:21][C@@H:19]([CH3:20])[CH2:18][C@H:17]([CH3:16])[O:14]2)[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)C[C@H](C)O
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C[C@@H]1CN(Cc2ccccc2)CCC12O[C@@H](C)C[C@H](C)O2

Procedure:
To a solution of 1-benzyl-3-methylpiperidin-4-one (Acros, 62.09 g, 305.4 mmol) and (2S,4S)-pentane-2,4-diol (TCI-US, 34.06 g, 327.0 mmol) in benzene (800 mL) was added p-toluenesulfonic acid mono hydrate (69.72 g, 404.9 mmol). The flask was fitted with a Dean-Stark trap and heated to reflux. The reaction mixture was cooled after 16 hours of reflux, concentrated to a total volume of about 500 mL and transferred to an Erlenmeyer flask with ethyl acetate. A sodium bicarbonate solution (500 mL) added with stirring and the mixture was further neutralized with solid Na2CO3 (35 g). The layers were partitioned, the organic phase washed with sodium bicarbonate, dried (Na2SO4) and concentrated to yield approximately 95 g of crude material. The residue was purified in 15 g batches by silica gel chromatography (Analogix SF-65-600 g; 35 micron silica; elution with 10% ethyl acetate-hexane) at 50 mL/min to provide 42.33 g of the first eluting isomer, (2S,4S,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane. 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.19 (m, 5H), 4.07-3.86 (m, 2H), 3.40 (ABq, 2H, JAB=13.5 Hz, δνAB=23.3 Hz), 2.41-2.20 (m, 4H), 1.90-1.76 (m, 2H), 1.59-1.47 (m, 3H), 1.12 (d, 3H, J=6.4 Hz), 1.11 (d, 3H, J=6.4 Hz), 0.90 (d, 3H, J=7.1 Hz); MS (DCI/NH3) m/e 290 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:49]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:48]=1)[C:38]([O:40][C@H:41]([CH3:45])[C@H:42](O)[CH3:43])=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1>[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:49]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:48]=1)[C:38]([O:40][C@H:41]([CH3:45])[C@H:42]([O:8][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[CH3:43])=[O:39])=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: C[C@@H](O)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of benzoic acid (0.57 g, 4.8 mmol) in anhydrous dichloromethane was added triethylamine (1.7 mL, 12 mmol), and 2,4,6-trichlorobenzoyl chloride (0.9 mL, 5.76 mmol) were added. The resulting mixture was stirred for 30 min and a solution of (1R,2R)-2-hydroxy-1-methylpropyl (2S)-2-[(tert -butoxy)carbonylamino]-3-[3,4-bis(phenyhnethoxy)phenyl]propanoate (2.4 g, 4.4 mmol) in dichloromethane was slowly added to the reaction mixture, followed by the addition of a catalytic amount of 4-(dimethylamino)pyridine. The resulting mixture was stirred at room temperature for 16 hrs, washed with 10% citric acid, dried over Na2SO4, and concentrated. Chromatography (silica gel, 20% ethyl acetate in hexane) of the residue afforded 2.6 g (90%) of (1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl (2S)-2-[(tert -butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate. 1H NMR (400 MHz, CDCl3): δ 1.26 (d, J=6.4 Hz, 6H), 1.39 (s, 9H), 2.78 (m, 1H), 2.96 (m, 1H), 4.51 (m, 1H), 4.89 (d, 1H), 5.10 (s, 4H), 5.15 (m, 1H), 6.57 (d, J=8 Hz, 1H), 6.71 (s, 1H), 6.77 (d, J=8 Hz, 1H), 7.25-7.43 (m, 12H), 7.52 (t, J=7.6 Hz, 1H), 7.99 (d, J=7.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)[CH3:2].[I-].[NH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12)=[O:14])[CH3:2]
Reactant: N[n+]1ccccc1
Reactant: CCOC(=O)C#Cc1cccc(C)n1
Agent: [I-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2cccc(C)n2)nn2ccccc12
Yield: 24.1 %

Procedure:
A solution of (6-methyl-pyridin-2-yl)-propynoic acid ethyl ester (0.62 g, 3.3 mmol) and 1-aminopyridinium iodide (0.8 g, 3.6 mmol) in acetonitrile (15 mL) is treated with DBU (0.5 mL, 3.3 mmol) and heated to reflux for 0.5 hours. The reaction is concentrated to a dark solid and purified by silica gel column chromatography (1:1 hexane/ethyl acetate) to afford 0.224 g (24%) of desired product as a yellow solid. MS ES+ m/e 282.2 (M+1). UV (95% EtOH) λmax 275 nm (ε 13005), 234 nm (ε 26550), 225 nm (ε 26057). TOF MS ES+ exact mass calculated for C11H11NO2 (p+1): m/z=282.1243. Found: 282.1244. Anal. Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.04; H, 5.28; N, 14.65.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(C=O)c(=O)n(-c2ccccc2)n1C
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: Cc1c(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c(=O)n(-c2ccccc2)n1C

Procedure:
Prepared by Procedure F and Scheme R using 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 447.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1([CH2:16][CH2:17][CH2:18][S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:12])[O:10]C(C)(C)[O:8][C:7]1=[O:15].[OH-].[Na+]>O1CCOCC1.O>[C:27]1([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19][CH2:18][CH2:17][CH2:16][C:6]([C:11]([OH:12])=[O:10])([C:7]([OH:15])=[O:8])[CH2:5][CH2:4][C:3]([OH:39])=[O:2])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CCC1(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)OC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)(C(=O)O)C(=O)O
Temperature: 100 °C

Procedure:
2.56 mmol of 2,2-dimethyl-4,6-dioxo-5-[3-[(triphenylmethyl)thio]propyl]-1,3-dioxane-5-propanoic acid methyl ester (II) (1.4 g) with 18 mmol of sodium hydroxide (0.72 g) was dissolved in a mixture of 5 ml of 1,4-dioxane and 5 ml of water. The mixture was then heated to 100° C. for 1 hour, evaporated to dryness, dissolved in water and precipitated by addition of 1 M sulfuric acid. The precipitate was filtered off, washed with water and dried in a dessicator. Yield 1.36 g of 6-[(triphenylmethyl)-thio ]-1,3,3-hexanetricarboxylic acid (III) (−100%), 13C-NMR (MeOH) δ 25.4, 29.2, 30.7, 33.5, 33.7, 58.0, 68.3, 128.1, 129.3, 131.2, 146.7, 174.9, 176.9.
Reaction SMILES: [N:1]1[CH:6]=C[CH:4]=[C:3]([O:7][C:8]2[CH2:12][CH2:11][O:10][N:9]=2)[CH:2]=1.OC1C=[N:16]C=NC=1.C(=O)CCC1C=CC=CC=1>>[N:1]1[CH:2]=[C:3]([O:7][C:8]2[CH2:12][CH2:11][O:10][N:9]=2)[CH:4]=[N:16][CH:6]=1
Reactant: Oc1cncnc1
Reactant: c1cncc(OC2=NOCC2)c1
Agent: O=CCCc1ccccc1
Product: c1ncc(OC2=NOCC2)cn1

Procedure:
3-(Pyrimidin-5-yloxy)-4,5-dihydroisoxazole III-54 was prepared in 3 steps from compound III-9 starting with the synthesis of 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-53 from compound III-9 and 5-hydroxypyrimidine using Method 5. Compound III-53 is then deprotected using analogous conditions to Example 11 and then converted to desired product III-54 using the analogous procedure as Example 13 except that hydrocinnamaldehyde was used in the place of benzoyl chloride. [M+H]+=367.6 m/z. Activity: B
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[N:17]1)[N:9]=[CH:8][N:7]=[CH:6]2.CN(C=O)C.S(Cl)([Cl:28])=O>>[Cl:28][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH:20]=[CH:19][N:18]=[N:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2cncnc2cc1OCCn1ccnn1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCn1ccnn1
Temperature: 80 °C
Yield: 71 %

Procedure:
A solution of 6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (920 mg, 3.2 mmol) in thionyl chloride (10 ml) containing DMF (0.9 ml) was heated at 80° C. for 1 hour. After evaporation of the volatiles, the residue was azeotroped with toluene. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with solid sodium hydrogen carbonate. The organic layer was washed with water, brine, dried (MgSO4), and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4) to give 4-chloro-6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (693 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[CH2:12](Br)[CH2:13]Br.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:13][CH2:12]1
Reactant: COc1ccccc1CC#N
Reactant: BrCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1C1(C#N)CC1
Reaction time: 20 h

Procedure:
A mixture of (2-methoxyphenyl)acetonitrile (147 g and 1,2-dibromomethane (168 ml) in dimethylsulphoxide (250 ml) was added over 1 hour to a stirred suspension of powdered potassium hydroxide (250 g) and 18-Crown-6 (5 g) in dimethylsulphoxide (1200 ml) at 25° C. Stirring was continued for 20 hours. Water (1200 ml) was added and the mixture extracted with ether to give a crude oil which was purified by distillation (b.p. 102°/0.25) to give 1-(2-methoxyphenyl)cyclopropane carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:27][C:28]([CH3:33])([CH3:32])[C:29]([NH2:31])=[O:30])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:27]([CH2:25][CH3:26])[C:28]([CH3:33])([CH3:32])[C:29](=[O:30])[N:31]=3)[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: CCNC(C)(C)C(N)=O
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: CCN1C(c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)=NC(=O)C1(C)C

Procedure:
Compound 7 was synthesized from 4a (251 mg, 0.66 mmol) and 5b (140 mg, 1.08 mmol) as a white solid (110 mg, 35%) in a manner similar to that described in Example 36. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, 1H), 7.28 (d, 2H), 7.25 (dd, H), 7.14 (d, 1H), 7.04 (d, 2H), 3.90 (q, 2H), 2.37 (s, 3H), 1.41 (s, 6H), 1.27 (t, 3H); ESMS m/z: 475.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:41]([O:43][C:44](=[O:48])[CH:45](Br)[CH3:46])[CH3:42]>C1COCC1.ClCCl>[CH2:41]([O:43][C:44](=[O:48])[CH:45]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:46])[CH3:42]
Reactant: O=C1Nc2ccccc2C1=Cc1ccc(O)c2ncccc12
Reactant: CCOC(=O)C(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 8-hydroxyquinoline-5-carbaldehyde (346 mg, 2 mmol), 2-oxindole (266 mg, 2 mmol) and piperidine (43 mg, 0.5 mmol) in absolute ethanol (10 ml) was heated for 3 h at 60-70° C. under nitrogen. Then the reaction mixture was chilled and evaporated under vacuum to dryness. The residue was submitted to column chromatography over silica gel using dichloromethane/ethanol 4% as eluant to give pure 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole in 60% yield (365 mg). To a solution of 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole (300 mg, 0.99 mmol) in THF (5 ml) was added at room temperature a solution of 1M tetrabutylammonium fluoride (5 ml) and 2-bromopropionic acid ethylester (0.9 ml, 6.9 mmol). The reaction mixture was stirred at room temperature for another 1 h and then diluted with dichloromethane. The organic layer was washed with 5% NaHCO3 solution and water, dried over sodium sulfate and then evaporated under vacuum. The oily residue was chromatographed on silica gel using ethyl acetate as eluant to give pure title compound in 86% yield (330 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.CS([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1)(=O)=O.[OH2:45]>C(#N)C>[OH:45][C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reaction time: 1 h

Procedure:
DIPEA (7.421 g, 10.00 mL, 57.42 mmol) was added to a suspension of 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (1 g, 1.918 mmol) in acetonitrile (20 mL). The reaction mixture was stirred for 1 hour then water (5 mL) was added. The mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give the desired product (880 mg, quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([OH:26])([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[CH:10]=[CH2:11].[H][H]>[Ni].C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)([OH:26])[CH2:10][CH3:11]
Reactant: [H][H]
Reactant: C=CC(O)(c1ccc(OCc2ccccc2)cc1)c1cc(C)ccc1C
Agent: [Ni]
Solvent: CCO
Product: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1cc(C)ccc1C

Procedure:
10.3 g. of 1-(2,5-dimethylphenyl)-1-(4-benzyloxyphenyl)-allyl alcohol are dissolved in 110 ml. of ethanol and the reaction mixture is hydrogenated under atmospheric pressure, in the presence of 3.5 g. of Raney nickel catalyst. After uptake of the calculated amount of hydrogen is complete, the catalyst is filtered off. Ethanol is distilled off under reduced pressure. As a residue 9 g. of the named compound are obtained as a viscous oil, boiling at 190°-192° C./26.6 Pa.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: OCC1CCCN1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCCC2CO)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
20 g of 5-fluoro-2-nitrotoluene, 14.3 g of 2-pyrrolidine methanol and 20 g of potassium carbonate were added to 100 ml of dimethylformamide. They were stirred at 100° C. for 2 h. After leaving to cool, the reaction mixture was poured into water. After extraction with ethyl acetate, the extract was washed with water, concentrated and recrystallized from acetonitrile to obtain 26 g of 2-hydroxymethyl-N-(3-methyl-4-nitrophenyl)pyrrolidine (d) as yellow crystals.