Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13](Cl)[C:12]3[C:16](=[O:30])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH3:29])[CH2:18][C:11]=3[C:10]=2[F:31])[CH2:6][CH2:5][O:4][CH2:3]1.[N:32]1[N:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]2=[C:34](B(O)O)[CH:33]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13]([C:34]3[CH:33]=[N:32][N:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=34)[C:12]3[C:16](=[O:30])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH3:29])[CH2:18][C:11]=3[C:10]=2[F:31])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Reactant: OB(O)c1cnn2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Temperature: 120 °C
Yield: 100.7 %

Procedure:
To a 5 mL microwave vial with a stir bar was added bis(triphenylphosphine)palladium chloride (11.68 mg, 0.017 mmol), 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (75 mg, 0.166 mmol), pyrazolo[1,5-a]pyridin-3-ylboronic acid (135 mg, 0.832 mmol) in dioxane (2 mL), and saturated aq NaHCO3 (2 mL). The mixture was heated in a Biotage Initiator microwave at 120° C. for 30 min. The mixture was concentrated and purified via preparative HPLC to give the title compound (89 mg, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.84 (m, 1H), 2.10-2.12 (m, 1H), 3.68-3.72 (m, 3H), 3.75 (s, 3H), 3.82 (s, 3H), 3.92-3.95 (m, 1H), 4.01-4.02 (m, 1H), 4.39 (s, 2H), 4.55-4.58 (m, 1H), 4.59 (s, 2H), 6.50 (dd, J=8.30, 1.95 Hz, 1H), 6.60 (d, J=2.44, 1H), 7.04-7.08 (m, 2H), 7.16 (d, J=5.86 Hz, 1H), 7.48-7.51 (m, 1H), 7.93 (br s, 1H), 8.37 (d, J=9.27 Hz, 1H), 8.79 (d, J=6.83 Hz, 1H), 9.36 (s, 1H). [M+H] calc'd for C28H29FN6O4, 533. found, 533.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[OH:20]>>[OH:20][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[CH2:18][NH:17][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(N)=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzamide (which was obtained in Example 147) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp >75° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.40 (m, 2H), 1.70-1.90 (m, 2H), 2.55-2.95 (m, 5H), 2.97 (s, 3H), 3.70-3.85 (m, 2H), 4.48 (dd, J=8.0, 4.3 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 6.99 (dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.67 (br s, 2H), 7.72 (d, J=9.0 Hz, 2H); MS (ES) m/z: 448.9 (MH+); HRMS Calcd. for C21H29N4O5S(MH+): 449.1853. Found: 449.1853.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:26]([OH:29])([CH3:28])[CH3:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([NH:30][S:31]([C:34]3[S:35][C:36]([Cl:39])=[CH:37][CH:38]=3)(=[O:33])=[O:32])=[N:18]2)[CH:13]=[CH:14][CH:15]=1.C([O:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46])(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CS(C)=O.CO>[Cl:39][C:36]1[S:35][C:34]([S:31]([NH:30][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:29])([CH3:27])[CH3:28])[N:17]([CH2:16][C:12]3[CH:11]=[C:10]([CH2:9][NH:8][C:45](=[O:46])[C:44]([OH:43])([CH3:49])[CH3:48])[CH:15]=[CH:14][CH:13]=3)[N:18]=2)(=[O:33])=[O:32])=[CH:38][CH:37]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CC(C)(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(O)C(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(C(C)(C)O)cccc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
Triethylamine (0.034 mL, 0.244 mmol) was added to N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(1-hydroxy-1-methylethyl)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 78) (40 mg, 0.081 mmol) in dichloromethane (1 mL). 2-Chloro-1,1-dimethyl-2-oxoethyl acetate (0.013 mL, 0.090 mmol) was added and the reaction mixture was stirred at room temp for 2 h. The reaction mixture was concentrated on the blowdown, potassium carbonate (113 mg, 0.815 mmol) and methanol (2 mL) was added and the reaction was stirred at room temp for 1 h. LCMS showed the acetate group was removed. The reaction mixture was concentrated, acidified with 2N HCl and extracted with EtOAc (2×15 mL). The combined organic layers were dried by passing through a hydrophobic frit and concentrated to afford the crude product as a yellow oil. The residue was dissolved in DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (11.5 mg, 24%). LCMS (System A) RT=1.05 min, ES+ve m/z 577/579 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:2]1([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: OCCC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: OCCC1CCN(c2nccc3ccccc23)CC1

Procedure:
4.17 g (25.50 mmol) of 1-chloroisoquinoline, 3.62 g (28 mmol) of 2-(4-piperidyl)ethanol, 5.90 g (61.20 mmol) of sodium tert-butoxide and 0.476 g (0.765 mmol) of BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) suspended in 50 ml of toluene are introduced under an inert atmosphere. 0.233 g (0.255 mmol) of tris(dibenzylideneacetone)dipalladium is then added. The reaction mixture is then refluxed for 12 hours.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([S:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:21].[CH3:22]O>>[ClH:21].[N:1]1[C:10]2[CH:9]([S:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:22])=[O:17])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(SC2CCCc3cccnc32)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(SC2CCCc3cccnc32)cc1
Yield: 62 %

Procedure:
4.24 g (15 mmol) of 4-(5,6,7,8-tetrahydroquinoline-8-ylthio)-benzoic acid prepared by a method analogous to Example 1 were stirred in 30 ml of refluxing methanol saturated with hydrogen chloride for 2 hours and the solvent was then removed under reduced pressure. The residue was dissolved in iced water, made alkaline with sodium carbonate and extracted with ether. The residue obtained upon evaporation of the solvent was treated with ethereal hydrogen chloride to yield 2.9 g (62%) of methyl 4-(5,6,7,8-tetrahydroquinoline-8-ylthio)-benzoate hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCN3CCN(c4ccccc4)CC3)C2)c1
Yield: 58.5 %

Procedure:
3-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]propanal (33.7 mg, 0.135 mmol), 1-phenylpiperazine (20.0 mg, 0.123 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (78.4 mg, 0.369 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 28.4 mg (58.4%) of the target compound was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Cl)=[CH:24][C:23]=1[O:31][CH3:32].C([O-])(O)=O.[Na+]>C(OCCCC)(=O)C>[OH:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)=[CH:24][C:23]=1[O:31][CH3:32]
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: COc1cc(CCCl)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCOC(C)=O
Product: COc1cc(CCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)ccc1O

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.1 g, 0.019 mole), 4-hydroxy-3-methoxyphenethyl chloride (4.25 g, 0.023 mole) and NaHCO3 (11 g) in 110 ml n-butyl acetate was heated at reflux for 18 hours. The reaction mixture was then cooled, filtered and concentrated to an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[N:30]=[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][NH:26][C:25](=O)[CH2:24]5)[N:16]4[N:15]=3)=[CH:10][CH:11]=2)[NH:6][N:5]=1.Cl.[OH2:32]>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[N:30]=[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][NH:26][CH2:25][C:24]5=[O:32])[N:16]4[N:15]=3)=[CH:10][CH:11]=2)[NH:6][N:5]=1
Reactant: O
Reactant: COCc1n[nH]c2cc(Nc3nc4cccc(CN5CCNC(=O)C5)n4n3)ccc12
Agent: Cl
Solvent: CCO
Product: COCc1n[nH]c2cc(Nc3nc4cccc(CN5CCNCC5=O)n4n3)ccc12
Temperature: 60 °C
Yield: 12 %

Procedure:
4-((2-(3-(Methoxymethyl)-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazin-2-one. 6 M HCl in water (0.410 mL, 2.459 mmol) was added to a stirred mixture of 4-((2-(3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)methyl)piperazin-2-one (0.132 g, 0.246 mmol) in ethanol (5 mL) at 60° C. The resulting mixture was stirred vigorously and heated at 60° C. under a reflux condenser under nitrogen for 12 h. The solvent was removed on a rotary evaporator. The residue was dissolved in hot DMSO, diluted with methanol, filtered, and purified using reverse-phase semi-preparatory HPLC (5-30% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 30 min). Fractions containing the desired product were loaded onto a Strata X—C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator and dried under high vacuum at 45° C. to give the desired product (0.012 g, 0.030 mmol, 12% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.67 (s, 1H), 9.86 (s, 1H), 8.19 (d, J=1.17 Hz, 1H), 7.86 (s, 1H), 7.51-7.65 (m, 3H), 7.24 (dd, J=1.76, 8.79 Hz, 1H), 7.11 (d, J=7.03 Hz, 1H), 4.66 (s, 2H), 4.11 (s, 2H), 3.29 (s, 3H), 3.17-3.27 (m, 4H), 2.80 (t, J=5.27 Hz, 2H); MS (ESI) m/z 407.5 [M+1]+.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([NH:25][CH:22]4[CH2:24][CH2:23]4)=[O:18])=[CH:20][CH:21]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: NC1CC1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)NC1CC1
Yield: 88.2 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and cyclopropylamine (0.039 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-cyclopropylacetamide as a white solid (0.198 g, 87.4% yield).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8]O)([CH2:6][OH:7])[CH2:4][OH:5].[Br:10]C(C(C)(C(Br)O)C)O.BrCC(CO)(CBr)CBr>>[CH2:4]([OH:5])[C:3]([CH2:2][Br:1])([CH2:8][Br:10])[CH2:6][OH:7]
Reactant: OCC(CO)(CO)CBr
Reactant: CC(C)(C(O)Br)C(O)Br
Agent: OCC(CBr)(CBr)CBr
Product: OCC(CO)(CBr)CBr

Procedure:
The compounds which constitute one of the starting reagents according to the present invention, consist of dibromoneopentyl glycol 2-bromomethyl-2-hydroxymethylpropane-1,3-diol, 2-bromomethyl-2-hydroxymethyl-1,3-dibromopropane, or mixtures thereof. As known, commercial DBNPG is obtained by the bromination of pentaerythritols. Depending on the method of operation, the product may be a relatively pure DBNPG or mixtures of 2-bromomethyl-2-hydroxymethylpropane-1,3-diol, 2,2-bis(bromomethyl)propane-1,3-diol, and 2-bromomethyl-2-hydroxymethyl-1,3-dibromopropane, wherein an average of 1.7 to 2.5 of the hydroxyls per molecule have been replaced by bromine. This represents a mixture of 2-bromomethyl-2-hydroxymethylpropane-1,3-diol,2,2-bis(bromomethyl)propane-1,3-diol and 2-bromomethyl-2-hydroxymethyl-1,3-dibromopropane whose concentration ranges vary from 5% 2-bromomethyl-2-hydroxymethylpropane-1,3-diol, 80% 2,2-bis(bromomethyl)propane-1,3-diol and 15% 2-bromomethyl-2-hydroxymethyl -1,3-dibromopane to 15% 2-bromomethyl-2-hydroxymethylpropane-1,3-diol, 80% 2,2-bis(bromomethyl)propane-1,3-diol, and 5% 2-bromomethyl-2-hydroxymethyl-1,3-dibromopropane. The residual hydroxyl groups of this mixture of compounds can also be readily hydroxymethylated. Therefore instead of utilizing pure DBNPG, the latter can be successfully replaced by the less expensive mixtures.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].F[C:17]1[CH:26]=[C:25]2[C:20]([C:21]([CH3:28])=[N:22][C:23]([NH2:27])=[N:24]2)=[CH:19][CH:18]=1>CN(C)C=O>[NH2:27][C:23]1[N:22]=[C:21]([CH3:28])[C:20]2[C:25](=[CH:26][C:17]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:18][CH:19]=2)[N:24]=1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Cc1nc(N)nc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3c(C)nc(N)nc3c2)c2c1C(=O)CC(C)(C)C2
Yield: 67.3 %

Procedure:
3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.7 g, 4 mmol), sodium hydride (60% in oil, 0.20 g, 4.8 mmol), 7-Fluoro-4-methyl-quinazolin-2-ylamine (0.7 g, 4 mmol), and N,N-dimethylformamide are heated at 150 degrees Celsius for 2 h. The mixture is extracted with ethyl acetate/water. The organic layer is dried and concentrated. The residue is purified by column chromatography, affording 0.9 g of a solid 1-(2-Amino-4-methyl-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (68%). LC/MS m/z=335 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33](=[O:50])[N:34]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[CH:35]2[CH2:38][C:39](O)=[O:40])=[CH:31][CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32](=[CH:31][CH:30]=1)[C:33](=[O:50])[N:34]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH:35]2[CH2:38][C:39]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:40]
Reactant: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)O)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
With ice-cooling and stirring, 1.57 g of 1,4-dioxa-8-azaspiro[4.5]decane, 2.3 ml of triethylamine and 2.12 g of diethyl phosphorocyanidate were successively added to a solution of 3.32 g of 6-chloro-2-(4-methoxyphenyl)-3-oxoisoindoline-1-acetic acid in 30 ml of dimethylformamide. The mixture was stirred with ice-cooling for an hour. To the reaction mixture was added 150 ml of ice water and the mixture was allowed to stand to give a crystalline precipitate, which was collected by filtration, washed with water and dried. Recrystallization from ether gave 4.13 g of colorless crystals melting at 156°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:17])[CH:10]([F:16])[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[OH-].[Na+].[N+:20]([C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)([O-:22])=[O:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:17][C:26]1[CH:27]=[CH:28][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=1)[CH:10]([F:16])[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC(c1ccc(Cl)cc1Cl)C(F)n1cncn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(OC(c2ccc(Cl)cc2Cl)C(F)n2cncn2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
With efficient stirring, 27.6 g of 1-(2,4-dichlorophenyl)-2-fluoro-2-(1H-1,2,4-triazolyl)ethanol (prepared in accordance with Example P1a) were added to a mixture of 250 ml of 2n NaOH solution, 250 ml of diethyl ether and 0.5 g of tetrabutylammonium bromide. 25 ml of 4-nitrofluorobenzene are added at 20° C. to this mixture, which is stirred for another 20 hours at room temperature. The separated ethereal phase is washed with water until neutral, dried over sodium sulfate, filtered and concentrated by evaporation. The crude oily product (35 g) is purified by chromatography through silica gel and melts after recrystallisation from diisopropyl ether/cyclohexanone at 98°-100° C.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=[O:18].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>[OH-].[Na+]>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[S:29]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]([OH:19])=[O:18])(=[O:30])=[O:31]
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: O=S(=O)(Cl)c1nc2ccccc2[nH]1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 56 h
Yield: 37.6 %

Procedure:
(2S)-2-Piperidinecarboxylic acid L-tartrate (42 g) [see Preparation 1] was dissolved in 10% w/w aqueous sodium hydroxide solution (600 ml) and 1H-benzo[d]imidazole-2-sulfonyl chloride (39 g) [see Preparation 8] was added. The reaction mixture was stirred at room temperature for 56 hours after which time the product was extracted with ethyl acetate. The organic layer was separated, 2N aqueous hydrochloric acid solution added and the acidic aqueous layer extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 95:5:0.5, by volume, dichloromethane:methanol:glacial acetic acid to afford 1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidinecarboxylic acid (17.5 g).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[CH:48][C:49]4[NH:54][C:53](=[O:55])[CH2:52][O:51][C:50]=4[N:56]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:47]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[CH:48][C:49]4[NH:54][C:53](=[O:55])[CH2:52][O:51][C:50]=4[N:56]=3)=[CH:44][CH:45]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Yield: 95 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (8 mg, 0.017 mmol) was reacted to afford the title compound (6 mg, 73%). LCMS (Method A): RT=3.59 min, M+1=373. 1H NMR (500 MHz, MeOD): 7.40 (2H, d), 7.37 (2H, d), 7.33 (1H, s), 7.32-7.28 (3H, m), 7.19-7.17 (2H, m), 4.93 (2H, s), 2.78-2.72 (2H, m), 2.60-2.54 (2H, m), 2.27-2.19 (1H, m), 2.00-1.91 (1H, m).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:16])=[CH:8][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)[C:21](O)=[O:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[Cl:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH:26]=[C:18]([F:17])[CH:19]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Reactant: Nc1ccc(OCCCl)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Yield: 81.9 %

Procedure:
4-(2-Chloroethoxy)-naphthalen-1-ylamine hydrochloride salt (482 mg, 1.86 mmol), 3-fluoro-5-piperidinylbenzoic acid (500 mg, 2.2 mmol), diisopropylethylamine (1.14 ml, 6.7 mmol) and HBTU (1.06 g, 2.8 mmol) are stirred at room temperature in anhydrous dimethylformamide (10 ml) for 1 day. The mixture is poured into ethyl acetate (200 ml) and washed with water (3×100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexanes to give N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide as a tan solid (650 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10](Cl)=[O:11].[NH2:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[C:26]([F:29])([F:28])[F:27]>>[CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([NH:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[C:26]([F:28])([F:27])[F:29])=[O:11]
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)Cl)[C@@H]1C2
Reactant: Nn1c(C(F)(F)F)nc2ccccc2c1=O
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)Nn3c(C(F)(F)F)nc4ccccc4c3=O)[C@@H]1C2

Procedure:
The product from Example 1C and 3-amino-2-(trifluoromethyl)quinazolin-4(3H)-one (Bionet) were processed using method analogous to that described in Example 1D to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.00 (d, J=9.8 Hz, 1H) 1.08 (s, 3H) 1.23 (d, J=5.1 Hz, 3H) 1.85-2.05 (m, 5H) 2.06-2.24 (m, 1H) 2.31-2.45 (m, 2H) 2.53-2.61 (m, 2H) 2.62-2.76 (m, 1H) 7.58 (s, 1H) 7.60-7.68 (m, 1H) 7.88 (d, J=3.7 Hz, 1H) 8.31 (d, J=7.8 Hz, 1H); MS (ESI+) m/z 394 (M+H)+.