Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][CH2:22]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1.[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][CH2:22]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCCc2ccccc21

Procedure:
A stirred mixture of N-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography over a silica gel column (SiO2, 40 g, eluted with methylene chloride DCM, and 1-3% MeOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170-171° C.
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([CH:33]=[N:34][N:35]=2)[C:7](SC)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[F:30])(=[O:3])[NH2:2].[Br-].[Cl:37][C:38]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:39]=1[CH2:40][Zn+].O1CCCC1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[C:5]2[N:6]([CH:33]=[N:34][N:35]=2)[C:7]([CH2:40][C:39]2[C:38]([Cl:37])=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:46])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[F:30])(=[O:3])[NH2:2]
Reactant: Clc1cccc(Cl)c1C[Zn+]
Reactant: CSc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(C(N)=O)c2nncn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)n4cnnc4c3C(N)=O)c(F)c2)CC1
Temperature: 70 °C

Procedure:
To a mixture of the product of Example 28E (200 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium (50 mg, 0.04 mmol) was added 0.5M 2,6-dichlorobenzylzinc bromide in tetrahydrofuran (4 mL, 2 mmol) under nitrogen atmosphere and the mixture was heated at 70° C. for 16 hours. After cooling to ambient temperature, the mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×20 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 97/3 dichloromethane/methanol to give the title compound. MS: 615 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.8 %

Procedure:
p-Methoxyaniline (0.078 g, 0.639 mmol), triethylamine (0.066 g, 0.639 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.108 g, 0.639 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.135 g, 0.318 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) and then recrystallized from ether to obtain the titled compound (0.040 g, 0.0756 mmol, 24%).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(F)c1Br
Agent: O=S(=O)(O)O
Product: O=C(O)c1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a 1 L, three necked flask fitted with a dropping funnel and a thermometer were charged 2-bromo-3-fluorobenzoic acid (Example 134g) (28.23 g, 0.13 mol) and concentrated H2SO4 (200 mL). After cooling to 0° C., HNO3 (70%, 16.0 mL) was added dropwise over 30 min, keeping the temperature between 0 to 10° C. After 1 h, the reaction mixture was poured into the crushed ice keeping the temperature below 20° C. The mixture was extracted with EtOAc (2×200 mL), the combined extract was washed with brine and dried with MgSO4. The filtrate was evaporated to give 27.27 g (77%) of a mixture of 2-bromo-3-fluoro-6-nitrobenzoic acid and 2-bromo-3-fluoro-5-nitrobenzoic acid (1:0.4) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J=9.6, 4.8 Hz, 1H), 7.21 (dd, J=10.0, 8.0 Hz, 1H).
Reaction SMILES: CSC.[S:4]1[C:8]([CH2:9][C:10]2[CH:11]=[C:12]([CH:22]3[C@@H:27]([O:28]CC4C=CC=CC=4)[C@@H:26]([O:36]CC4C=CC=CC=4)[C@@H:25]([O:44]CC4C=CC=CC=4)[C@@H:24]([CH2:52][O:53]CC4C=CC=CC=4)[O:23]3)[C:13]3[C:18]([C:19]=2[O:20][CH3:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:6]2[CH:61]=[CH:62][CH:63]=[CH:64][C:5]1=2.O>C(Cl)Cl>[S:4]1[C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@H:22]3[C@H:27]([OH:28])[C@@H:26]([OH:36])[C@H:25]([OH:44])[C@@H:24]([CH2:52][OH:53])[O:23]3)[C:13]3[C:18]([C:19]=2[O:20][CH3:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:6]2[CH:61]=[CH:62][CH:63]=[CH:64][C:5]1=2
Reactant: COc1c(Cc2cc3ccccc3s2)cc(C2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c2ccccc12
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: COc1c(Cc2cc3ccccc3s2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.3 %

Procedure:
Under a nitrogen atmosphere, dimethylsulfide (1.6 ml) and a boron trifluoride-diethyl ether complex (0.79 ml, 6.23 mmol) were added to a solution of (3R,4R,5S,6R)-2-[3-(benzo[b]thiophen-2-ylmethyl)-4-methoxynaphthalen-1-yl]-3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydropyran (515 mg, 0.62 mmol) in methylene chloride (10 ml) under cooling with ice. The reaction mixture was stirred at room temperature for three days, then water (10 ml) was added under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried with sodium sulfate, and thereafter the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (20:1)] to obtain the title compound (82 mg, 28%).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH2:26][CH3:27])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>>[CH:28]1([CH2:31][NH:32][C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[O:25][CH2:26][CH3:27])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:30][CH2:29]1
Reactant: CCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: NCC1CC1
Product: CCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC3CC3)c2n1
Yield: 5 %

Procedure:
The title compound was prepared according to the method described for Example 99 using 8-chloro-N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 114) and cyclopropanemethylamine for 5 hours. The residue was further purified by passage through a SCX-2 cartridge eluting with 100% MeOH—0.5 M NH3 in MeOH to give the title compound (2.6 mg, 5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.Cl.[CH3:35][O:36][NH2:37]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:37][O:36][CH3:35])[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON
Reactant: C#CCOc1ccc(CCNC(=O)C(=O)c2ccc(Cl)c(Cl)c2)cc1OC
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C#CCOc1ccc(CCNC(=O)C(=NOC)c2ccc(Cl)c(Cl)c2)cc1OC

Procedure:
To a solution of 1.30 g (3.20 mmol) 2-(3,4-dichloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-oxo-acetamide in 7.0 ml ethanol, 0.52 ml pyridine (0.64 mmol) and 0.33 g (3.98 mmol) O-methylhydroxylamine hydrochloride are added. The solution is heated at +80° C. for 4 hours. After evaporation of the solvent, the residue is submitted to flash-chromatography to yield the 2-(3,4-dichloro-phenyl)-2-methoxyimino-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide as a white solid (m.p. 107-108° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:34][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33].[OH2:42]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:34][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[C:17]2[C:12](=[CH:13][C:14]([C:4]3[O:42][CH:7]=[CH:2][CH:3]=3)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33]
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Reactant: O
Solvent: Cc1ccccc1
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(-c2ccco2)cc3C(F)(F)F)C1

Procedure:
A solution of the compound of Example 14-1 (140 mg, 0.188 mmol), 2-tributyltinfuran (80 mg, 0.224 mmol) and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol) in toluene (5 mL) was stirred at 100° C. under nitrogen for 3 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (chloroform/methanol=20/1) to give the titled compound (80 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[S:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=2[S:6][C:7]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc2ccc(Cl)cc2c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc2ccc(Cl)cc2c1CBr

Procedure:
A mixture of ethyl 5-chloro-3-methylbenzo(b)thiophene-2-carboxylate (9.0 g, 0.035 mol), N-bromosuccinimide (6.53 g, 0.037 mol) and benzoyl peroxide (130 mg) in carbon tetrachloride (150 ml) was refluxed and illuminated with a sunlamp for 2 hours. The resulting suspension was cooled, filtered and the filter cake was triturated with methanol to give 9.9 g, (85%) of the methanol-insoluble ethyl 3-bromomethyl-5-chlorobenzo(b)thiophene-2-carboxylate: mp 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](O)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.[OH-].[NH4+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: COc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Reactant: CCCCCCCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(OC)cc32)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 14.82 grams of 8-methoxy-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin in 50 milliliters of benzene was added 12.55 grams of caprylic acid (octanoic acid). The resulting reaction mixture was allowed to stand overnight and was then heated for 3 hours at a temperature of 60°C. After cooling, the mixture was shaken with 100 milliliters of water, 20 milliliters of concentrated aqueous ammonium hydroxide solution was then added thereto, and the mixture was extracted with a mixture of benzene and ethyl ether. The resulting extract was washed with water, dried over anhydrous potassium carbonate, and the solvent was evaporated therefrom. The residue was dissolved in 40 milliliters of acetone and added to a solution of 9.5 grams of maleic acid in 30 milliliters of acetone. On standing, 15.5 grams of crude 8-methoxy-10-]4-(3-octanoyloxypropyl)piperazino]-10,11-dihydrobenzo[b,f]thiepin di(hydrogen maleate) crystals separated therefrom. On purification by recrystallization from acetone, the di(hydrogen maleate) salt had a melting point of 130°C. The free base was recovered in the form of a viscous oil by adding the di(hydrogen maleate) to a dilute aqueous ammonium hydroxide solution and extracting the solution with benzene as described in Example 1 hereinbefore.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[H-].[Na+].F.[OH-:20].[Na+].[CH3:22][N:23]([CH3:26])C=O>C(#N)C.O>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:6][C@H:7]([OH:20])[CH2:8][CH2:9][C:4]3[CH:26]=[N:23][CH:22]=[CH:2][CH:1]=3)=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)c1cccc(-c2ccc(O)cc2)c1
Reactant: [OH-]
Agent: F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Prepared according to method described in Example 26e) from 3'-acetylbiphenyl-4-ol (Example 55b), 0.59 g), (2R)-4-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-(4-toluenesulfonyloxy)butane (1.0 g) and sodium hydride (60% dispersion in mineral oil, 0.12 g) in dry N,N-dimethylformamide (10 ml). Crude material from this reaction was dissolved in acetonitrile (15 ml) and treated with hydrofluoric acid (40%, 5 ml). The reaction mixture was stirred at room temperature for 18 hours and then poured into water (25 ml). The pH was adjusted to 9 by adding sodium hydroxide solution (2 M). The mixture was then extracted with ethyl acetate (3×100 ml) and the combined extracts dried over anhydrous magnesium sulfate. The solution was filtered and then concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a white solid (0.25 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 55.5 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (2.42 g), ethyl 3-(3-hydroxyphenyl)propionate (1.35 g), anhydrous potassium carbonate (0.97 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.82 g, 55%) of ethyl 3-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 90-91° C.
Reaction SMILES: CS(Cl)(=O)=O.[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH3:24])[C:22]([CH2:25][C:26]([CH3:29])(O)[CH3:27])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][N:23]1[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:18]=2)=[CH:20][N:21]=[C:22]1[CH:25]=[C:26]([CH3:29])[CH3:27]
Reactant: Cn1c(-c2ccnc(Nc3ccccc3)n2)cnc1CC(C)(C)O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Reaction time: 3 h
Yield: 41.4 %

Procedure:
Methanesulphonyl chloride (151 μl, 1.96 mmol), was added to a solution of 2-anilino-4-(1-methyl-2-(2-methyl-2-hydroxypropyl)imidazol-5-yl)pyrimidine (Method 97; 600 mg, 1.86 mmol), and triethylamine (777 μl, 5.58 mmol), in DCM (10 ml), at ambient temperature under nitrogen. The mixture was stirred for 3 hours then adsorbed directly onto silica gel and purified by chromatography eluting with EtOAc to give the title compound (235 mg, 42%). NMR: 1.98 (s, 3H), 2.14 (s, 3H), 3.99 (s, 3H), 6.24 (s, 1H), 6.98 (t, 1H), 7.10 (d, 1H), 7.28 (dd, 2H), 7.69-7.72 (m, 3H), 8.40 (d, 1H), 9.42 (s, 1H); m/z: 306.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:34](=[O:37])[CH:35]=[CH2:36])[CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13])(C)(C)C.C(Cl)(=O)C=C.C(OC(=O)NCCNC(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C.CCN(CC)CC>C(Cl)Cl>[CH2:25]([N:24]1[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:11]([N:10]1[C:34](=[O:37])[CH2:35][CH2:36][NH:7][CH2:8][CH2:9]1)[CH:12]([CH3:13])[CH3:14])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=CC(=O)N(CCNC(=O)OC(C)(C)C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Agent: C=CC(=O)Cl
Agent: CC(C)C(NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-{Acryloyl-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-amino}-ethyl)-carbamic acid tert-butyl ester: Acryloyl chloride (126 μL, 1.6 mmol) was added to {2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester (500 mg, 1.03 mmol) and Et3N (216 μL, 0.15 mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (10 mL), washed with brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (10% EtOAc/hexane) gave the title compound (310 mg) as a white solid: MS (ES) m/e 539.2 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23]CCCCCC.[CH2:30]1[N:35]2[CH2:36]C[N:32]([CH2:33][CH2:34]2)[CH2:31]1.O>C(#N)C.CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([N:32]4[CH2:33][CH:34]5[CH2:23][CH:31]4[CH2:30][N:35]5[CH3:36])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1CN2CCN1CC2
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CCCCCCC
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1c(F)c(N2CC3CC2CN3C)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
0.93 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.5 g of 2-methyl-2,5-diazabicyolo[2.2.1]heptane and 0.36 g of DABCO are refluxed for 2 hours in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide. At room temperature, the reaction mixture is treated with 2 ml of water, and the solid is filtered off with suction, washed with water and dried. 0.9 g of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2-methyl-2,5-diazabicyclo[2.2.1]hept-5-yl)-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[N:22]4)[CH:8]3[N:9]=2)=[C:5]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[N:4]=[CH:3]1.S(Cl)(Cl)=O.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH:25]=[C:24]([C:26]([NH:41][CH:38]5[CH2:40][CH2:39]5)=[O:27])[CH:23]=[N:22]4)[CH:8]3[N:9]=2)=[C:5]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[N:4]=[CH:3]1
Reactant: NN1C=NC(c2ccco2)=C2C1=NC1N(CCn3cc(C(=O)O)cn3)C(=O)N(CC3CC3)N21
Reactant: NC1CC1
Solvent: O=S(Cl)Cl
Product: NN1C=NC(c2ccco2)=C2C1=NC1N(CCn3cc(C(=O)NC4CC4)cn3)C(=O)N(CC3CC3)N21
Temperature: 75 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
A mixture of 1-[2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl]pyrazole-4-carboxylic acid (0.050 g, 0.111 mmol) was taken in thionyl chloride (0.04 ml, 0.557 mmol) and stirred at 75° C. for 2 hours. The reaction mixture was concentrated and residue was dissolved in DCM (2 ml). To the above solution cyclopropyl amine (0.015 ml, 0.222 mmol) was added at 0° C. and stirred at same temperature for 2 hours and filtered to obtain 1-[2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl]-N-cyclopropyl-pyrazole-4-carboxamide (5.0 mg, 9%) as an off white solid.