Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH3:26])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>N1C=CC=CC=1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH3:26])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)C(=O)Cl
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)cc1C
Solvent: c1ccncc1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(OC(=O)C(C)C)cc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 36 %

Procedure:
3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (2.0 g, 5.7 mmol) was suspended in pyridine (25 ml), isobutyryl choride (5 ml) added, and the mixture stirred for 17 hours at room temperature; the solid rapidly dissolved to give a clear solution. The pyridine was evaporated, and the residue taken up in dichloromethane and washed with aqueous sodium bicarbonate and brine, dried and evaporated. Recrystallisation from isopropyl ether gave 3-butyryl-4-(4-isobutyryloxy-2-methylphenylamino)-8-methoxyquinoline (0.87 g, 36%), m.p. 123°-125°.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[CH:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:23]([CH:20]([CH3:22])[CH3:21])[C:24]=1[NH:25][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])([CH3:32])[CH3:31]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Yield: 94.8 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.20 g of Compound A and 1.00 g of 2,6-diisopropylaniline in place of aniline to obtain 1.85 g of Compound 4.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.C(OCC)C>O1CCCC1>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[CH:4]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(Cl)c(Cl)cc1Br
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(Cl)c(Cl)cc2F)OC1(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
1-Bromo-4,5-dichloro-2-fluorobenzene (1.0 g, 4.11 mmol) was dissolved in tetrahydrofuran (THF; 20 mL) and cooled to −10° C. A 2.0M solution of isopropylmagnesium chloride (2.3 mL, 4.6 mmol) in THF was added dropwise via a syringe. The reaction mixture was stirred at −10° C. for 1 hour, allowed to warm toward 0° C. for 1 hour, then cooled to −10° C. again. A solution of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (0.85 g, 4.56 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.85 g, 71% yield) that was used without further purification: 1H NMR (CDCl3): δ 7.73 (d, 1H), 7.12 (d, 1H), 1.3 (s, 12H).
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[C:21]([C:44]([F:47])([F:46])[F:45])=[CH:22][C:23]2[O:28][C:27]([CH3:35])([CH2:29][O:30][CH2:31][CH:32]3[CH2:34][O:33]3)[C:26](=[O:36])[N:25]([CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:24]=2[CH:43]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)([CH3:3])[CH3:2].[O-:48][CH2:49][CH3:50].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH2:49]([O:48][CH2:34][CH:32]([OH:33])[CH2:31][O:30][CH2:29][C:27]1([CH3:35])[C:26](=[O:36])[N:25]([CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:24]2[CH:43]=[C:20]([C:18]([N:4]([CH:1]([CH3:2])[CH3:3])[C@@H:5]3[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6]3)=[O:19])[C:21]([C:44]([F:47])([F:45])[F:46])=[CH:22][C:23]=2[O:28]1)[CH3:50]
Reactant: CC[O-]
Reactant: COCCCCN1C(=O)C(C)(COCC2CO2)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(O)COCC1(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2N(CCCCOC)C1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2-methyl-2-[(oxiran-2-ylmethoxy)methyl]-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-amino)piperidine-1-carboxylate (113 mg) in tetrahydrofuran (1 ml) was added sodium ethoxide (0.1 ml, 20% ethanol solution), and the mixture was stirred at 50° C. for 2 hours. The reaction solution was cooled, and thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. To the obtained residue was added acetic acid (1 ml), and the mixture was stirred at 50° C. for one hour. The solution was cooled to room temperature, and thereto was added ethyl acetate, and the organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:43]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:44])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C1CCCC1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)C1CCCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure D using cyclopentanecarbonyl chloride. The final product was obtained in 52% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].C[N:20](C)C=O.CC(O)C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:20])[C:7]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccncc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Solvent: CC(C)O
Product: Nc1ccc(C(=O)c2ccncc2)cc1[N+](=O)[O-]

Procedure:
The procedure of Example 24 was followed except 4-(3-nitro-4-chlorobenzoyl)pyridine was used in place of 3-(3-nitro-4-chlorobenzoyl)pyridine. The product was orange prisms, mp. 294° -295° C. (dimethylformamide-2-propanol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].CC(C)([O-])C.[K+].[F:17][C:18]([F:22])([F:21])[CH2:19][OH:20]>>[F:17][C:18]([F:22])([F:21])[CH2:19][O:20][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1ccnc(OCC(F)(F)F)c1
Temperature: 170 °C
Reaction time: 120 h

Procedure:
A mixture consisting of 7.5 g of 2-chloroisonicotinic acid, 16 g of potassium tert-butoxide and 100 ml of 2,2,2-trifluoroethanol was stirred at 170° C. for 5 days in a sealed tube. After evaporation of the solvent, the residue was mixed with water and 4 N hydrochloric acid and extracted with chloroform. The solvent was washed with water, dried over anhydrous magnesium sulfate and then concentrated, and the thus formed crystals were washed with hexane to obtain 7.7 g of the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29](O)[C:30]#[N:31])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O=S(Cl)[Cl:35]>C(Cl)(Cl)Cl.CN(C=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29]([Cl:35])[C:30]#[N:31])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(-c2ccc3cc(C(O)C#N)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc3cc(C(Cl)C#N)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
To a solution of 2-[6-(3-[1-adamantyl]-4-methoxyphenyl)-2-naphthyl]-2-hydroxy-acetonitrile, (0.314 mg, 0.74 mmol) in anhydrous chloroform (10 mL) were added SOCl2 (0.17 mL, 2.23 mmol) and DMF (3 drops). The reaction mixture was heated under reflux for 40 minutes before it was allowed to cool down, washed with water, saturated NaHCO3, brine to give 2-[6-(3-[1-adamantyl]-4-methoxyphenyl)-2-naphthyl]-2-chloro-acetonitrile that was used without further purification.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O:5]=[C:6]1[C:11]2[CH:12]=[CH:13]O[C:10]=2[CH2:9][CH2:8][CH2:7]1.C(OC(C)C)(C)C>C(O)C>[O:5]=[C:6]1[CH2:7][CH2:8][CH2:9][C:10]2[N:4]([CH2:3][CH2:1][OH:2])[CH:13]=[CH:12][C:11]1=2
Reactant: O=C1CCCc2occc21
Reactant: NCCO
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: O=C1CCCc2c1ccn2CCO
Temperature: 130 °C
Yield: 83.8 %

Procedure:
80 g of ethanolamine were added to a solution of 136 g of 4-oxo-4,5,6,7-tetrahydrobenzofuran in 250 cm3 of ethanol. The solution was heated at 130° C. for 6 hours. After allowing the reaction mixture to return to room temperature with stirring, the mixture was poured over a mixture of 800 cm3 of isopropyl ether and 200 cm3 of petroleum ether. A product crystallized with stirring, and then it was drained, washed with petroleum ether and dried under vacuum over phosphorus pentoxide. 160 g of the expected product was recovered, which product was recrystallized from 240 cm3 of isopropanol. 150 g of the expected product was obtained whose melting point ranged from 96° to 97° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](C(C)(C)C)=[C:6]([CH:10]=[CH:11][C:12]=1Cl)[C:7]([O-:9])=[O:8])([O-:3])=[O:2].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][O:27][C:26]2=[O:35])[CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][O:27][C:26]2=[O:35])[CH2:23][CH2:24]1)[C:7]([O:9][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:8])([O-:3])=[O:2]
Reactant: CC(C)(C)c1c(C(=O)[O-])ccc(Cl)c1[N+](=O)[O-]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
The product was prepared from 3-nitro-4-chloro-t-butylbenzoate (0.96 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (1.0 g) using the method of example 115 step (ii). Purification was by chromatography eluting with 50% ethyl acetate/isohexane. Yield 2.1 g as an oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:32])[CH3:31])=[C:9]2[N:8]=1)[CH2:4][CH3:5].N[C@@H](CO)[C@H](C)[OH:36]>>[OH:1][CH2:2][C@@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:19][CH:20]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:31])[CH3:32])=[C:9]2[N:8]=1)[C@H:4]([OH:36])[CH3:5]
Reactant: C[C@H](O)[C@@H](N)CO
Reactant: CC[C@H](CO)Nc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Product: CC(C)c1cnn2c(NCc3ccc(-c4ccccn4)cc3)nc(N[C@H](CO)[C@@H](C)O)nc12
Yield: 42 %

Procedure:
According to the same conditions resulting in the preparation of the compound 2, the compound 12 is prepared from IIa.2 by oxidation reaction of the sulfur atom and then introduction of D-threoninol. Yield=42%, Oil. 1H NMR (300 MHz, CDCl3): δ 8.69 (d, 1H, J=4.7 Hz, Harom), 7.97 (d, 2H, J=8.3 Hz, Harom), 7.78-7.69 (m, 2H, Harom) 7.63 (s, 1H, 1H, Harom), 7.45 (d, 2H, J=8.3 Hz, Harom), 7.26-7.21 (m, 1H, Harom), 6.71 (bs, 1H, NH), 5.62 (d, 1H, J=6.6 Hz, NH), 4.77 (d, 2H, J=6.0 Hz, CH2), 4.22-4.15 (m, 1H, CH), 3.97-3.84 (m, 3H, CH 4-CH2), 3.01 (hept, 1H, J=7.0 Hz, CH), 1.29 (d, 3H, J=6.2 Hz, CH3), 1.28 (d, 6H, J=7.0 Hz, 2 CH3). MS (EST): m/z 448 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.CN1CCOCC1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32]Br.C(O)C(N)(CO)CO>CN(C)C=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Fc1ccc(CBr)cc1F
Agent: NC(CO)(CO)CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(OCC3CCN(Cc4ccc(F)c(F)c4)CC3)cccc2n1
Reaction time: 2 h
Yield: 41.7 %

Procedure:
5-(Piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was shaken for 60 hours at 60° C. in the presence of 3-(morpholino)propyl polystyrene sulfonamide (PS-NMM) (160 mg; 0.4 mmol) and 3,4-difluorobenzyl bromide (77 mg; 0.37 mmol) in 4 mL N,N-dimethylformamide. Tris-(2-aminoethyl)aminomethyl polystyrene (PS-Trisamine) (112 mg; 0.4 mmol) was then added to the mixture and continued to shake for an additional 2 hours. Resins were filtered off and rinsed with methanol. Filtrate was concentrated at reduced pressure, and residue was triturated with 2 mL 1 N NaOH and ethanol (1:1). Solids were collected by filtration to yield 5-[1-(3,4-difluorobenzyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine (30 mg; 42% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.61 (m, 2H), 7.34 (m, 2H), 7.14 (m, 2H), 6.76 (m, 1H), 6.52 (m, 1H), 5.94 (br s, 2H), 3.99 (d, J=6.0 Hz, 2H), 3.46 (s, 3H), 3.12 (m, 1H), 2.82 (br d, J=10.8 Hz, 1H), 2.11 (m, 2H), 1.95 (m, 2H), 1.73 (br d, J=11.2 Hz, 1H), 1.34 (m, 1H). MS m/z (ESI) 400 (M+H)+.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3][CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([OH:10])[CH2:3][CH2:2]2
Reactant: O=C1CCN2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OC1CCN2CCC1CC2
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To 1-azabicyclo[3.2.2]nonan-4-one (0.20 g, 1.4 mmol) in 1,4-dioxane (2.8 mL) at 0° C. was added lithium aluminum hydride [1.0M/THF] (1.7 mL, 1.7 mmol). The reaction mixture was maintained at 0° C. for 15 minutes. The reaction was quenched by the stepwise addition of 46 □L of H2O, 46 □L of 15% aqueous NaOH, and 138 □L of H2O. The mixture was filtered through Celite which was subsequently washed with EtOAc. The solvent was removed in vacuo to afford the product (0.19 g, 96%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.90-3.86 (m, 1H), 3.09-3.03 (m, 1H), 2.96-2.91 (dd, J=9.2, 6.8 Hz, 1H), 2.86-2.75 (m, 3H), 2.71-2.64 (m, 1H), 2.34-2.27 (bs s, 1H), 1.98-1.86 (m, 3H), 1.71-1.59 (m, 3H), 1.51-1.35 (m, 1H) ppm.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=O)[CH:21]=1>>[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH:4][CH2:1][C:2]#[CH:3])=[O:26])[CH:21]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)O)cn1
Reactant: C#CCN
Product: C#CCNC(=O)c1ccccc1-n1cnc(-c2c(-c3ccccc3)noc2C)c1
Yield: 25 %

Procedure:
As described for Example 71, prop-2-ynylamine was converted, using 2-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (28 mg, 25%) which was obtained as an off-white solid. MS: m/e=383.1 [M+H]+.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[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>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc2ccccc2n1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1ccc2ccccc2n1)NO
Reaction time: 48 h
Yield: 76 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (90 mg, 0.24 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 48 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4) to furnish IV as a colourless oil (66.43 mg, 76%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:11][C:12](=O)[CH2:13][CH2:14][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18]>>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]2[N:4]([CH:11]=[C:12]([CH2:13][CH2:14][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)[CH:5]=1
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Reactant: Nc1ncc(F)cc1F
Product: C[Si](C)(C)C#CCCc1cn2cc(F)cc(F)c2n1
Yield: 49.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 223(D), from 3,5-difluoropyridin-2-amine (492 mg, 3.78 mmol) and 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 1.87 mg, 7.56 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, from DCM/Cyclohexane: 70/30 to DCM/MeOH: 95/5 as eluent) to afford 517 mg of 6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 49%) as a brown oil.
Reaction SMILES: C[N:2]1[CH:6]2[CH2:7][C:8]([CH2:10][CH:3]1[CH2:4][CH2:5]2)=[O:9].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1C=CC=CC=1>[CH2:15]([O:14][C:12]([N:2]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH2:10][C:8](=[O:9])[CH2:7]2)=[O:13])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: CN1C2CCC1CC(=O)C2
Solvent: c1ccccc1
Product: CCOC(=O)N1C2CCC1CC(=O)C2
Yield: 88.4 %

Procedure:
56.5 g of tropinone are dissolved in 330 ml of anhydrous benzene and heatedto 70° C. under a nitrogen atmosphere. A solution of 88 g of freshly-distilled ethyl chloroformate in 200 ml of benzene is added dropwise within one hour, with stirring. After a further 4 hours' heating under reflux, cooling is effected, followed by filtration; the filtrate isconcentrated in a vacuum, and the residue is purified by vacuum distillation to obtain 70.75 g (88.4 percent) of (e) as colorless oil (b.p. 91° to 93° C. at 12 Pa.)
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[NH2:18].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(OCC)(=O)C>[F:20][C:7]([F:6])([F:19])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[NH:18][C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccnc2ccc(C(F)(F)F)cc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccnc2ccc(C(F)(F)F)cc12)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A rapidly stirred mixture of ethyl acetate and saturated aqueous sodium bicarbonate containing commercially available 6-(trifluoromethyl)quinolin-4-amine (558 mg, 2.63 mmol) was cooled to 0° C. and treated dropwise with benzyl chloroformate (1.10 mL, 3.29 mmol). After stirring overnight warming to room temperature, the aqueous layer was removed and the organic layer concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, 0-20% MeOH/Ethyl acetate) yielded the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13]
Reactant: O=C=Nc1ccccc1Br
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Cl)c1
Reaction time: 24 h
Yield: 67.3 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-bromophenyl isocyanate (0.62 ml, 5.01 mmol) in THF (20 ml) was added Et3N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-bromophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 24 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 4-[N′-(2bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 67%) as a colorless powder. 1H-NMR (CDCl3) δ3.58 (s, 3H), 3.70 (s, 2H), 6.98 (m, 3H), 7.19 (dd, J=8.3, 1.9 Hz, 1H), 7.32 (m, 1H), 7.51 (m, 2H),k 8.05 (m, 1H); MS (ESI) m/z 398 (M++1), 400 (M++3), 402 (M++5).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1ccncc1
Product: c1ccc2c(-c3ccncc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-pyridinylboronic acid to give ((1H-pyrazol-3-yl)-(1-pyridin-4-yl-isoquinolin-3-yl)-amine. LC-MS m/e 288(MH+).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C@H:10]1[CH2:25][CH3:26])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@@H:9]([OH:8])[C@@H:10]2[CH2:25][CH3:26])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chloro-3-methylbenzonitrile (650 mg) in tetrahydrofuran (20 mL)-methanol (10 mL) was added 6 mol/L hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/9) to give the title compound as a colorless solid (yield: 227.1 mg, 49%).