Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:21]2[N:25]([CH3:26])[N:24]=[C:23]([O:27][CH2:28][CH2:29][OH:30])[C:22]=2[C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)COCCOC)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:21]2[N:25]([CH3:26])[N:24]=[C:23]([O:27][CH2:28][CH2:29][OH:30])[C:22]=2[C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOCN(c1c(-c2ccc(C(F)(F)F)cc2)c(OCCO)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: Cn1nc(OCCO)c(-c2ccc(C(F)(F)F)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 8 h

Procedure:
To 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N-[(2-methoxyethoxy)methyl]benzenesulfonamide (Preparation 12) in ethanol (1.5 ml) was added hydrochloric acid (6M, 1.5 ml). The reaction mixture was refluxed for 5 hours and then left at room temperature overnight. The reaction was concentrated under reduced pressure and the residue was partitioned between water (10 ml) and ethyl acetate (10 ml). The aqueous was extracted with ethyl acetate (2×20 ml). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired product (120 mg) as a white solid. Taken on crude to the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7](Cl)[N:6]=[C:5]([Cl:10])[N:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[NH2:16].C(Cl)Cl.[K+].[Br-]>>[CH3:23][O:22][C:18]1[CH:17]=[C:15]([NH:16][C:7]2[N:8]=[C:3]([NH:2][CH3:1])[N:4]=[C:5]([Cl:10])[N:6]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:19]=1[O:20][CH3:21]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CNc1nc(Cl)nc(Cl)n1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Cl)nc(Nc2cc(OC)c(OC)c(OC)c2)n1
Yield: 65 %

Procedure:
The title compound was synthesized from 2-methylamino-4,6-dichloro-1,3,5-triazine and 3,4,5-trimethoxyaniline using a similar procedure to the one used in 2. Yield: 65%; Tm 237° C.; FTIR (CH2Cl2/KBr) 3270, 3134, 3051, 2964, 2940, 2842, 2831, 1658, 1631, 1612, 1588, 1567, 1535, 1502, 1453, 1422, 1390, 1351, 1297, 1264, 1230, 1201, 1189, 1172, 1128, 1082, 1057, 1034, 997, 978, 924, 882, 830, 809, 735, 704, 679 cm−1; 1H NMR (300 MHz, DMSO-d6, 298 K) δ 9.97, 9.77 (s, s, 1H), 8.09, 7.91 (s, s, 1H), 7.21, 7.09 (s, s, 2H), 3.74 (s, 6H), 3.61 (s, 3H), 2.86, 2.80 (d, d, 3J=4.6 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 167.4, 165.8, 165.6, 163.3, 162.9, 152.5, 135.0, 134.8, 133.2, 133.0, 98.2, 97.6, 60.0, 55.8, 55.5, 27.4, 27.2 ppm; HRMS (EI) calcd. for C13H16ClN5O3 (m/e): 325.0942. found: 325.0934.
Reaction SMILES: O[N:2]=[C:3]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:5]([C:6](=[O:30])[O:7][C:8]3[C@H:9]4[C@:21]([CH3:29])([CH2:22][CH2:23][C:24]=32)[C@@H:12]([C@@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]4)[CH2:4]1.S(Cl)(Cl)=[O:32].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:28][C@:25]12[CH2:26][CH2:27][NH:2][C:3](=[O:32])[CH2:4][C@@H:5]1[C:6](=[O:30])[O:7][C:8]1[C@@H:9]3[CH2:10][CH2:11][C@H:12]([C@@H:13]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:20])[C@@:21]3([CH3:29])[CH2:22][CH2:23][C:24]=12
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=NO)CC1C(=O)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCNC(=O)C[C@@H]1C(=O)O3
Reaction time: 1 h
Yield: 27.9 %

Procedure:
Compound 3 (41.5 mg, 0.0999 mmol) obtained in Example 3 was dissolved in 1,4-dioxane (3.0 mL), and thionyl chloride (21.9 μL, 0.300 mmol) was added thereto at room temperature, followed by stirring for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative thin layer chromatography to obtain the title compound (11.6 mg, 28%).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:5]1[OH:15])=[N+:2]=[N-:3].BrC1CCN(C(OCC)=O)CC1O[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>>[N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:5]1[O:15][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[N+:2]=[N-:3]
Reactant: CCOC(=O)N1CCC(Br)C(O[Si](C)(C)C(C)(C)C)C1
Reactant: CCOC(=O)N1CCC(N=[N+]=[N-])C(O)C1
Product: CCOC(=O)N1CCC(N=[N+]=[N-])C(O[Si](C)(C)C(C)(C)C)C1

Procedure:
The title compound was prepared in a manner analogous to (Intermediate 238) starting with ethyl 4-bromo-3-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1-carboxylate (Intermediate 241). MS (GC-EI)[(M-N2)+]: 300 for C14H28N4O3Si.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C@H:26]3[CH2:28][C@H:27]3[CH2:29][CH2:30]O)[CH2:22][CH2:21]2)=[N:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:13][C:14]1[CH:15]=[N:16][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C@H:26]3[CH2:28][C@H:27]3[CH2:29][CH2:30][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=3)[CH2:22][CH2:21]2)=[N:18][CH:19]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (4-hydroxyphenyl)acetate (106 mg, 0.639 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (150 mg, 0.532 mmol) in 5 ml anhydrous dichloromethane, triphenylphosphine (polymer-bound, 419 mg, 1.21 mmol), and di-test-butyl azodicarboxylate (245 mg, 1.07 mmol). The reaction mixture was stirred at RT for 3 hours. It was filtered by Celite® and concentrated. The residue was purified by column chromatography on silica gel (50 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 430.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][CH2:5][CH3:6].[C:7]([CH:10]1[CH2:13][N:12]([C:14](=[O:28])/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:24](=[N:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)[CH2:11]1)(=O)[CH3:8]>CO.ClCCl>[O:28]=[C:14]([N:12]1[CH2:13][CH:10](/[C:7](=[N:2]\[O:3][CH2:4][CH2:5][CH3:6])/[CH3:8])[CH2:11]1)/[CH:15]=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:24](=[N:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2
Reactant: CCCON
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCO/N=C(/C)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h

Procedure:
1-(Amino-oxy)-propane hydrochloride (32 mg, 0.29 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (61.3 mg, 0.20 mmol) in a mixture methanol/dichloromethane (8:2, 3.5 mL) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol (95:5) as eluent. The title product was obtained as a white solid (56.0 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[Al+3].[Cl-].[Cl-].[Cl-]>[C]=S>[Cl:9][CH2:10][CH2:11][C:12]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:8])[CH:4]=1)=[O:13]
Reactant: Cc1ccccc1Cl
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [C]=S
Agent: [Cl-]
Product: Cc1cc(C(=O)CCCl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
23.43 ml of 2-chlorotoluene and 26.6 g of 3-chloropropionyl chloride are mixed in 25 ml of carbon sulfide and 32 g of AlCl3 in 125 ml of carbon sulfide are added over 45 minutes. After stirring for 3 hours at RT, the solvent is evaporated and then 1 liter of water is added. The reaction medium is extracted with ether and then with benzene, and then the organic phase is washed with a saturated Na2CO3 solution and then with water. It is dried over Na2SO4 and then the residue is chromatographed on a silica column, eluting with an AcOEt/cyclohexane (5/95; v/v) mixture. 27.25 g of the expected compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH:8](Cl)[NH:7][CH:6]=[CH:5]2.C([NH2:21])(=O)C.C([O-])([O-])=O.[K+].[K+]>C(OC(=O)C)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[C:8]([NH2:21])=[N:7][CH:6]=[CH:5]2
Reactant: CC(N)=O
Reactant: FC(F)(F)Oc1cc2c(cc1Br)C=CNC2Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nccc2cc(Br)c(OC(F)(F)F)cc12
Temperature: 180 °C
Yield: 24.2 %

Procedure:
4 g (12 mmol) of 6-Bromo-1-chloro-7-trifluoromethoxy-2H-isoquinoline are intermixed with 14 g acetamide (14 eq.) and 5 g (3 eq.) K2CO3. This mixture is heated for 1 h at 180° C. under stirring. The reaction mixture is stirred in ethylacetate (100 ml) and water (100 ml). The organic phase is separated, dried with Na2SO4 and the solvent removed under reduced pressure after filtration of the drying agent. For purification, a chromatography on silical gel (40-63μ, Merck) is performed with ethylacetate as mobile phase. 890 mg of a solid are obtained.
Reaction SMILES: CC1O[C:4]2([N:25]3[CH2:30][CH2:29]OCC3)[CH:9]([CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[C:11]=1[N+:12]([O-:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]2.N.Cl>C(O)C.O>[CH3:29][C:30]1[NH:25][C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:23])([F:22])[F:24])[C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: CC1=C([N+](=O)[O-])C(c2ccccc2C(F)(F)F)C2CCCCC2(N2CCOCC2)O1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CC1=C([N+](=O)[O-])C(c2ccccc2C(F)(F)F)C2=C(CCCC2)N1

Procedure:
2 g (4.7 mmol) of 2-methyl-8a-morpholino-3-nitro-4-(2-trifluoromethylphenyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene are suspended in 15 ml of ethanol and dissolved with about 3 ml of concentrated aqueous ammonia solution at 30° to 45° C. The pH is then brought to 3 with concentrated hydrochloric acid and the solution is diluted with 5 ml of water and extracted twice with 10 ml of chloroform each time. After the chloroform has been evaporated off, the residue crystallizes in yellow crystals from a little ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 4-fluoro-3-nitrophenol (8.1 g, 38 mmol) and 2-(chloromethyl)quinoline (6.0 g, 38 mmol) in DMF (100 mL) were added K2CO3 (21 g, 153 mmol) followed by KI (317 mg, 1.9 mmol). The mixture was stirred at 50° C. for 5 h. The mixture was cooled to RT, water (100 mL) was added, and the mixture was extracted with EtOAc (3×150 mL). The organics were combined, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=9, 1H), 8.15 (d, J=9, 1H), 7.87 (d, J=9, 1H), 7.80-7.72 (m, 2H), 7.65-7.56 (m, 2H), 7.32-7.26 (m, 1H), 7.23-7.16 (m, 1H), 5.44 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:14][NH:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[C:8]=2[CH3:13])[N:3]=1.Br[CH2:29][C:30]#[CH:31].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(O)C.CO>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:14][N:15]([CH2:31][C:30]#[CH:29])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[C:8]=2[CH3:13])[N:3]=1
Reactant: COc1cc(NCc2ccc3nc(N)[nH]c(=O)c3c2C)cc(OC)c1OC
Reactant: C#CCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCO
Product: C#CCN(Cc1ccc2nc(N)[nH]c(=O)c2c1C)c1cc(OC)c(OC)c(OC)c1

Procedure:
A suspension of 0.10 g (0.27 mmol) of 2-amino-5-methyl-6-[[(3,4,5-trimethoxyphenyl)amino]methyl]-4(3H)-quinazolinone, (see Example P) 0.54 ml (2.7 mmol) of an 80% solution of 3-bromo-1-propyne in toluene, and 0.42 ml (3.0 mmol) of triethylamine in 10 ml of ethanol is heated under reflux for eighteen hours. The solution is cooled, concentrated, and combined with material obtained from a similar experiment also using 0.10 g of starting material. The residue is dissolved in methanol and treated with 10 g of flash silica gel. The methanol is evaporated and the powder is applied to a column of 100 g of flash silica gel packed in dichloromethane/methanol (50:1). Elution with the same solvent initially, gradually increasing the polarity to dichloromethane/methanol (10:1) gives 0.07 g of a glassy material. Two recrystallizations from ethanol gives 0.0196 g (8.5%) of the product as an off-white solid, mp 202°-204° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:53][C@H:54]([C:59]([O:61][CH2:62][CH2:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[C:76]([C:77]#[N:78])=[C:75]([N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)[N:74]=[C:73]([S:84][CH2:85][C:86]3[N:87]=[C:88]([C:91]4[CH:96]=[CH:95][C:94]([Cl:97])=[CH:93][CH:92]=4)[S:89][CH:90]=3)[C:72]=2[C:98]#[N:99])=[CH:67][CH:66]=1)=[O:60])[CH2:55][CH:56]([CH3:58])[CH3:57]>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:53][C@H:54]([C:59]([O:61][CH2:62][CH2:63][O:64][C:65]1[CH:66]=[CH:67][C:68]([C:71]2[C:76]([C:77]#[N:78])=[C:75]([N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)[N:74]=[C:73]([S:84][CH2:85][C:86]3[N:87]=[C:88]([C:91]4[CH:96]=[CH:95][C:94]([Cl:97])=[CH:93][CH:92]=4)[S:89][CH:90]=3)[C:72]=2[C:98]#[N:99])=[CH:69][CH:70]=1)=[O:60])[CH2:55][CH:56]([CH3:57])[CH3:58])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1

Procedure:
86 mg (0.45 mmol) of N-(tert-butoxycarbonyl)-L-alanine were initially charged in 5.0 ml of DMF, and 95 mg (0.49 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 95 mg (0.62 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 266.13 g (2.06 mmol) of N,N-diisopropylethylamine were added. The mixture was stirred until a clear solution had been obtained. 330 mg (0.41 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl L-leucinate trifluoroacetate were then added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was added to 300 ml of water. The residue formed was filtered off with suction and washed with 20 ml of water. The crude product was suspended in 15 ml of methanol and sonicated in an ultrasonic bath for 5 min. The residue was filtered off with suction and washed with 10 ml of diethyl ether. This gave 0.15 g (43% of theory) of the desired target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH2:18]1[C:22]2[CH2:23][NH:24][CH2:25][C:21]=2[CH2:20][N:19]1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:25][C:21]3[CH2:20][N:19]([C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:35])([F:37])[F:36])=[O:27])[CH2:18][C:22]=3[CH2:23]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc([N+](=O)[O-])cn1)C2

Procedure:
2-Chloro-5-nitropyridine (510 mg, 3.22 mmol), (3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (1.046 g, 2.64 mmol) and cesium carbonate (1.72 g, 5.28 mmol) were stirred in 20 ml of DMF at 80° C. for 5 h. After concentrating under reduced pressure, ethyl acetate and water were added, and the precipitated solid was filtered off with suction. The organic phase was removed and concentrated. The two precipitates were combined. Yield: 845 mg (79%), M+H+: 405.04.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[S].ClC1C=C(C)C=CC=1Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:14][CH:15]=1
Reactant: O=C1CCCCC1=Cc1ccc(Cl)cc1
Agent: Cc1ccc(Cl)c(Cl)c1
Agent: [S]
Solvent: Cc1ccccc1
Product: Oc1ccccc1Cc1ccc(Cl)cc1
Temperature: 200 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
In a 50-ml, eggplant-shaped flask equipped with a magnetic stirrer and a reflux condenser were placed 6.6 g (30 mmole) of the 2-(4-chlorobenzylidene)cyclohexanone obtained in Example 12, 1.44 g (45 mmole) of sulfur and 12 ml of 3,4-dichlorotoluene in this order. The system was made vacuum using an aspirator and then returned to ordinary pressure using nitrogen; and this operation was repeated three times. The system was stirred for 4 hours at a bath temperature of 200° C. and then cooled to room temperature. 50 ml of toluene was added to the system, followed by extraction with 50 ml of a 10% aqueous sodium hydroxide solution; and this operation was repeated twice. The aqueous layer was washed with 50 ml of toluene. Then, 35% hydrochloric acid was added to the aqueous layer until the aqueous layer became acidic, followed by extraction with 50 ml of ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then subjected to vacuum distillation to remove ethyl acetate, to obtain 1.5 g of a brown oil. The oil was subjected to Kugel Rohr distillation to obtain 0.6 g of light yellow crystals. Yield: 9% The purity of the intended product in the crystal was 97.8% as measured by high performance liquid chromatography.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][N:16]=2)[C:7]1=[O:32])C>C(O)C>[CH:5]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][N:16]=2)[C:7]1=[O:32])=[O:4]
Reactant: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2ccccc21
Agent: Cl
Solvent: CCO
Product: COCCOc1cc2ncnc(C3C(=O)N(C=O)c4ccccc43)c2cc1OC
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
2M Hydrochloric acid (0.54 ml, 1.08 mmol) was added to a solution of 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (250 mg, 0.53 mmol), (prepared as described in Example 2), in ethanol (10 ml) at ambient temperature. A precipitate rapidly appeared. The mixture was stirred for 30 minutes, the solid was collected by filtration washed with ethanol and then ether and dried under vacuum at 60° C. to give 4-(1-formyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (141 mg, 68%) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:8](=[O:23])[CH:7]=1.C1C(=O)N([Cl:36])C(=O)C1>ClC(Cl)C(O)=O.ClC(Cl)C>[Cl:36][C:7]1[C:8](=[O:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O
Yield: 51.6 %

Procedure:
3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from above) (7.5 g, 19.4 mmol) and NCS (2.6 g, 19.4 mmol) were taken up in 65° C. dichloroethane (100 ml). A catalytic amount of dichloroacetic acid (2 drops) was added. After two hours the solvent was removed in vacuo and the residue was taken up in diethyl ether. The precipitate was collected on a filter pad and then taken up in 50% ethyl acetate/hexanes to remove residual succinimide. The precipitate was collected on a filter pad and then dried in vacuo to produce a white powder (4.2 g, 52%). 1H NMR (300 MHz, CD3OD) δ 8.10 (dd, J=7.85 1.81 Hz, 1H), 7.83 (d, J=8.26, 1.81 Hz, 1H), 7.40 (app q, J=8.26 Hz, 1H), 7.58 (d, J=7.85 Hz, 1H), 7.13-7.06 (m, 2H), 6.74 (s, 1H), 5.40 (s, 2H), 2.14 (s, 3H), 2.04 (s, 3H); ES-MS m/z 420 (M+H). ES-HRMS m/z 420.0786 (M+H calcd for C21H17ClF2NO4 requires 420.0809).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:40])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23](CC)[CH2:24][C:25]4C=CC(OC)=CC=4)[C:20]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:41].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:40])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:41]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
(+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (390 mg, 0.681 mmol) was mixed with anisole (0.372 mL, 3.40 mmol) and DCE (3 mL). TFA (1.049 mL, 13.61 mmol) was added and the mixture was stirred at 25° C. for 1 hr. The mixture was concentrated to dryness under high-vac. 30 ml 2N NH3/MeOH was added and stirred for 30 min. The white precipitate was collected by filtration and washed with 20 ml cold MeOH, ether, and dried under air-suction for 2 hrs to give rac-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (193 mg).
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]2)[CH2:3][NH:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[CH:28]=[N:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][C:31]=3I)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[CH:28]=[N:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][C:31]=3[N:2]2[CH2:1][CH:9]3[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]3)[CH2:3]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Reactant: O=S(=O)(c1ccc(F)cc1)c1cnc2c(I)cccc2c1
Product: CC(C)(C)OC(=O)N1CCC2CN(c3cccc4cc(S(=O)(=O)c5ccc(F)cc5)cnc34)CC2C1
Yield: 55 %

Procedure:
The title compound was prepared by analogy to the procedure of Example 1.3, except using tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate and 3-(4-fluorophenylsulfonyl)-8-iodoquinoline. 130 mg (55%) of the title compound were obtained as a pale yellow oil.