Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11](OC)=[O:12])=[CH:10][C:4]=2[N:3]=1.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2[nH]c(C)nc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2cc(CO)ccc2[nH]1
Temperature: 20 °C

Procedure:
27.8 g (10.146 mol) of 18b in 500 ml of THF are treated with 365.4 ml (0.438 mol) of DIBAL (20% strength solution in toluene) at -70° C. overnight in analogy to Example 1a. The crude product is vigorously stirred in boiling ethyl acetate and, after cooling to 20° C., the remaining material is filtered off with suction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22](N)=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-:25].[K+].Cl.[OH-].[Na+]>O.C(O)CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([OH:25])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: Cc1ccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
A mixture of 100 parts of 4-[(4-methylphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxamide, 52.2 parts of potassium hydroxide and 638 parts of 1,2-ethanediol is stirred and refluxed for 25 hours. After cooling, 1200 parts of water are added and the whole is acidified with a concentrated hydrochloric acid solution. The acid aqueous phase is alkalized with a sodium hydroxide solution 60%: exothermic reaction. After cooling, the precipitated crude product is filtered off and dissolved in water. This solution is acidified with acetic acid (pH about 6.5) and the product is filtered off. It is crystallized from N,N-dimethylformamide, filtered off again, washed with 2-propanone and dried, yielding 4-[(4-methylphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylic acid; mp. 270° C.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][OH:42])=[CH:36][CH:35]=1>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:42][CH2:41][CH2:40][C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCc1ccncc1
Product: CC1=C(C(=O)OCCc2ccncc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml 2-(4-pyridinyl)ethanol. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([F:39])=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C(O)C.C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([F:39])=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1ccc(F)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1ccc(F)c2ccccc12
Reaction time: 1 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(4-fluoro-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate (160 mg, 0.293 mmol) in ethanol (2 mL) and THF (2 mL) was added LiOH (2.0 N in water, 2.93 mL, 5.86 mmol), then the mixture was stirred for one hour. The mixture was diluted with DCM, then acidified with 2.0 N HCl (aq). The layers were separated, then the organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to obtain the title compound as a white solid. 1H NMR (499 MHz, CD3OD): δ 8.40 (d, J=8.8 Hz, 1H); 7.92 (d, J=8.3 Hz, 1H); 7.70 (dd, J=8.2, 5.3 Hz, 1H); 7.60 (d, J=8.3 Hz, 2H); 7.55 (t, J=7.6 Hz, 1H); 7.50 (d, J=8.1 Hz, 2H); 7.45 (t, J=7.6 Hz, 1H); 7.39 (d, J=8.1 Hz, 2H); 7.30 (d, J=8.3 Hz, 2H); 7.00 (dd, J=10.4, 8.2 Hz, 1H); 5.19 (d, J=11.5 Hz, 1H); 3.52 (t, J=6.9 Hz, 2H); 3.36-330 (m, 1H); 2.53 (t, J=7.0 Hz, 2H); 1.62 (d, J=10.4 Hz, 2H); 1.11-1.05 (m, 2H); 0.78 (t, J=7.3 Hz, 3H). LC3 4.01 min. [M+H]+ 518.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cc(F)c(F)cc1F
Product: O=C(O)Cc1ccccc1Nc1cc(F)c(F)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,4,5-triflouroaniline to yield 2-[(2,4,5-triflourophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl.Cl.[OH:3][CH:4]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]=1[F:28])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14].Br[CH2:30][CH2:31][S:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1.[C:38](=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.CN(C=O)C.C(N(CC)CC)C>[OH:3][CH:4]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]=1[F:28])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:30][CH2:31][S:32][C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[CH2:9][CH:8]1[C:13]([O:15][CH3:38])=[O:14]
Reactant: COc1ccc2ncc(F)c(C(O)CCC3CCNCC3C(=O)O)c2c1
Reactant: BrCCSc1cccs1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)C1CN(CCSc2cccs2)CCC1CCC(O)c1c(F)cnc2ccc(OC)cc12
Temperature: 65 °C
Reaction time: 15 h

Procedure:
0.74-cm3 of triethylamine was added to a solution composed of 1.17 g of methyl (3RS, 4RS) 4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)piperidine-3-carboxylate dihydrochloride in 20-cm3 of acetonitrile and 10-cm3 of DMF, followed by 638 mg of 2-(2-bromoethylthio)thiophene in 10-cm3 of acetonitrile, 1 g of potassium carbonate and 431 mg of potassium iodide. The mixture was stirred for 15 hours at a temperature in the region of 65° C. under an inert atmosphere. After cooling to about 20° C., the reaction mixture was filtered on sintered glass. The filtrate was taken up in 100-cm3of acetonitrile and concentrated under reduced pressure (5 kPa). The residue was taken up in 200-cm3 of ethyl acetate and 100-cm3 of water. The organic phase was separated after settling out, washed with twice 75-cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 μ; diameter 2 cm; height 40 cm), eluting with a mixture of cyclohexane-ethyl acetate (25/75 by volume) and collecting 50-cm3 fractions. Fractions 6 to 8 were concentrated. 630 mg of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylate were obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:40]1[CH2:45][CH2:44][O:43][CH2:42][CH:41]1[C:46]1[C:54]2[S:53][C:52]([NH2:55])=[N:51][C:50]=2[C:49]([O:56][CH3:57])=[CH:48][CH:47]=1>C1COCC1.C(Cl)(Cl)Cl>[O:40]1[CH2:45][CH2:44][O:43][CH2:42][CH:41]1[C:46]1[C:54]2[S:53][C:52]([NH:55][C:4](=[O:6])[CH2:3][O:2][CH3:1])=[N:51][C:50]=2[C:49]([O:56][CH3:57])=[CH:48][CH:47]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1

Procedure:
From methoxyacetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.9° (c=1.05, CHCl3), ES-MS m/e (%): 339 (M+H+, 100).
Reaction SMILES: C[O:2][CH:3]([Cl:5])Cl.[CH3:6][CH:7]([CH3:14])[CH2:8][C:9](=[O:13])C(O)=O>>[CH3:6][CH:7]([CH3:14])[CH2:8][C:9](=[O:13])[C:3]([Cl:5])=[O:2]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: COC(Cl)Cl
Product: CC(C)CC(=O)C(=O)Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
30.4 g (264 mmol) of dichloromethyl methyl ether were added slowly to 34.4 g (264 mmol) of 4-methyl-2-oxovaleric acid and the mixture was heated to 50° C. (bath temp.). After stirring for 60 min. at this temperature, the crude product was fractionated on a vigreux column to give the 4-methyl-2-oxovaleryl chloride (b.p. 41° C./14 mbar). 14.7 g (99 mmol) of 4-methyl-2-oxovaleryl chloride were dissolved in 144 ml of tetrahydrofuran and the solution was added dropwise at 0° C. to a solution of 6.66 g (45 mmol) of the polyester of Example 6 (monomer unit 2c) and 7.83 g (99 mmol) of pyridine in 514 ml of tetrahydrofuran/dimethylformamide (5:1). The reaction mixture was stirred at 0° C. for additional 3 hours, then filtered through Hyflo Cel and the filtrate was concentrated under reduced pressure. The polymeric product was precipitated by dropwise addition of the resulting solution into 1000 ml of isopropyl ether/n-hexane (1.5:1). The precipitate was stirred several times in tetrahydrofuran/diethyl ether (1:2) and the insoluble part was removed by filtration. The resulting clear solution was added dropwise into 500 ml of isopropyl ether, the precipitate was redissolved in tetrahydrofuran and precipitated from 1000 ml of n-hexane giving a polyester having the monomer unit 11c.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=1>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: N#Cc1cc(Br)cs1
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-bromo-2-cyanothiophene generally according to the procedures described in examples 82 and 1. A yellowish solid: mp 202-204° C.; 1H NMR (DMSO-d6): δ 10.06 (s, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 7.64-7.7 (m, 2H), 7.55 (d, J=5.0 Hz, 1H), 7.23 (d, J=8.48 Hz, 1H), 6.92-7.03 (m, 2H), 4.06 (d, J=15.52 Hz, 1H), 3.94 (d, J=15.44 Hz, 1H), 3.37 (m, 1H), 2.5 (m, 1H), 0.76 (t, J=6.79 Hz, 1H); MS (ESI) m/z 381 ([M+H]+); MS (ESI) m/z 379 ([M−H]−); Anal. calcd for C20H16N2O2S2: C, 63.14; H, 4.24; N, 7.36. Found: C, 62.53; H, 4.25; N, 7.12.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][C:23]([OH:25])=[O:24]>O1CCCC1>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:23]([OH:25])(=[O:24])[CH2:22][OH:20]
Reactant: O=C(O)CBr
Agent: OCc1nn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CO

Procedure:
2.4 g of sodium hydride (60% suspension in oil) are added to a solution of all the amount of 1-benzyl-3-hydroxymethylindazole obtained as described above, in 70 ml of tetrahydrofuran and the reaction mixture is heated to reflux under a stream of an inert gas (nitrogen). A solution of 3.5 g of bromoacetic acid in 40 ml of tetrahydrofuran is then added and the reaction mixture is refluxed for 90 minutes. After cooling, the reaction mixture is worked out in a standard manner and acidified. The resulting product is recrystallized from isopropanol. The ether of 1-benzyl-3-hydroxymethylindazole with glycolic acid is thus obtained (Compound I, R =R'=R'"=H), m.p. 136°-138° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14]4=[N:19][S:25](=[O:27])(=[O:26])[CH2:24][CH2:23][N:15]4[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(C2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(C4CCCCC4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A mixture of 3-(4-cyclohexylphenyl)pyridin-2-amine (57 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 45.2 mg) and 2-chloroethanesulfonyl chloride (110 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (40.3 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH:17]([OH:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].B.CSC.CO>C1COCC1>[CH2:4]([O:3][C:1]([N:11]1[CH:12]([CH2:13][OH:14])[CH2:16][CH:17]([OH:19])[CH2:18]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: O=C(OCc1ccccc1)N1CC(O)CC1CO
Temperature: 25 °C

Procedure:
To a solution of N-CBz-4-hydroxy-L-proline (38.1 mmol) in 250 ml THF was added borane-methyl sulfide (78 mmol) dropwise at room temperature. After the evolution of H2 had ceased, the solution was heated to reflux with mechanical stirring. After 1 hour a white precipitate had formed. Methanol was carefully added, and the resulting solution refluxed for a further 15 minutes. The solution was cooled to room temperature, the solvents evaporated under reduced pressure, and the residual gum coevaporated with 2×100 ml MeOH. The product was obtained as a viscous oil in quantitative yield and identified by NMR.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[Si:14]([O:21][CH2:22][CH:23]=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C([BH3-])#N.C(O)(=O)C>CN(C=O)C>[Si:14]([O:21][CH2:22][CH2:23][NH:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCNCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 150 °C
Yield: 10.5 %

Procedure:
To a mixture of 2-(aminomethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (50 mg, 0.28 mmol) and 2-(tert-butyldimethylsilyloxy)acetaldehyde (53 uL, 0.28 mmol) in DMF (1 mL) was added siliabond cyanoborohydride (300 mg, 0.30 mmol, 1 mmol/g) and acetic acid (0.158 mL, 2.8 mmol). The mixture was heated via microwave at 150° C. for 5 minutes, concentrated in vacuo and the resulting material was purified via HPLC to provide the title compound (10 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ 4.51 (s, 2 H), 3.87 (t, J=5.5 Hz, 2H), 3.71 (s, 2H), 3.58-3.68 (m, 2H), 2.62 (ddd, J=14.7, 5.3, 5.1 Hz, 4H), 0.82 (s, 9H), 0.00 (s, 6H). Retention time=1.52 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11]Br)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:13]#[N:14].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:13]#[N:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: BrCC1(c2ccc(Br)cc2)CC1
Reactant: [C-]#N
Agent: [K+]
Product: N#CCC1(c2ccc(Br)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 2, using 1-bromo-4-(1-bromomethyl-cyclopropyl)-benzene and potassium cyanide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH:21]([CH:23]1[CH2:25][CH2:24]1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=S)C=1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[CH:23]1([CH:21]=[C:9]2[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=[C:10]23)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1C(O)C1CC1
Agent: CN(C)c1ccncc1
Agent: S=C(n1ccnc1)n1ccnc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1=CC1CC1
Temperature: 25 °C

Procedure:
A solution of 100 mg (0.28 mmol) of [7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro [1,2,4]triazolo[1,5-α]pyrazin-8-yl](cyclopropyl)methanol (prepared as outlined in Example 3, Step A), 52.4 mg (0.294 mmol) of 1,1-thiocarbonyldiimidazole, and 3.4 mg (0.028 mmol) of 4-(dimethylamino)pyridine in 2.0 mL of dichloroethane was stirred at reflux temperature for 17 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The aqueous phase was extracted with three portions of ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated. Purification by preparative TLC (silica gel) gave the title compound as a clear semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:26][CH2:25][O:24][CH3:23])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COCCBr
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Oc3ccc(Cl)cc3F)c2cc1OC
Temperature: 180 °C
Yield: 68.6 %

Procedure:
A mixture of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), 2-bromoethyl methyl ether (83 mg, 0.6 mmol) and potassium carbonate (207 mg. 1.5 mmol) in DMF (3 ml) was heated at 180° C. for 45 minutes. The reaction mixture was allowed to cool, diluted with water and acidified to pH3.5. This aqueous mixture was extracted with ethyl acetate and the organic extract was washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/ether (7/3) to give 4-(4-chloro-2-fluorophenoxy)-7-(2-methoxyethoxy)-6-methoxyquinazoline (130 mg, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[N:10]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)#[CH:26].C(N(CC)CC)C>O1CCCC1.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.[Cu]I>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[N:10]=2)=[C:2]([C:26]#[C:25][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH:7]=1
Reactant: Clc1ccc(-c2nc3ccccc3n2CC2CCCCC2)c(Br)c1
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C#Cc2cc(Cl)ccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of 2-(2-bromo-4-chloro-phenyl)-1-cyclohexylmethyl-1H-benzoimidazole (0.56 g, 1.38 mmol) in dry tetrahydrofuran (8 ml) were added 4-ethynyl-benzonitrile (0.22 mg, 1.7 mmol; CAS Reg. No. 3032-92-6), bis(triphenylphosphine)palladium(ii) dichloride (63 mg, 0.09 mmol), copper(I) iodide (8 mg, 0.04 mmol) and triethyl amine (10 ml) at 25° C. in a sealed tube. The resulting mixture was degassed and back-filled with nitrogen three times. It was then allowed to stir at 80° C. for 16 h. The reaction mixture was filtered through a bed of celite, concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (20-25 ethyl acetate/n-hexane) to afford the desired compound as an off-white powder (38%). MS (Turbo Spray): m/z=450.0 (M+H).
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[C:13]1([S:19]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)(Cl)(Cl)[Cl:22]>>[C:13]1([S:19][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:4])=[O:5])[CH2:2][Cl:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CS(=O)(=O)c1ccc(Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Reactant: ClSc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCl)Sc1ccccc1

Procedure:
A solution of 29.4 g (0.145 mole) of p-chlorophenyl vinyl sulfone in 50 ml of carbon tetrachloride at 22° was treated with 21.0 g (0.145 mole) of benzenesulfenyl chloride. There was an exotherm to 32°. The solution was removed at reduced pressure and the residue recrystallized from benzene to give product of m.p. 108.5°-109.5° C.
Reaction SMILES: [N:1](=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:21]([CH2:28][CH2:29][CH2:30][CH3:31])[S:22][N:23]([CH3:27])[C:24](F)=[O:25])[CH2:18][CH2:19][CH3:20]>C(#N)C>[CH2:17]([N:21]([CH2:28][CH2:29][CH2:30][CH3:31])[S:22][N:23]([CH3:27])[C:24]([O:2][N:1]=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])=[O:25])[CH2:18][CH2:19][CH3:20]
Reactant: CC1=NC(C)(C)SC1=NO
Reactant: CCCCN(CCCC)SN(C)C(=O)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(CCCC)SN(C)C(=O)ON=C1SC(C)(C)N=C1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.0 g (0.019 mol) of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime are suspended in 10 ml of absolute acetonitrile. To the suspension at 0° C. there are successively added 5.5 g of anhydrous potassium carbonate and, dropwise, a solution of 4.52 g of N-(di-n-butylaminosulphenyl)-N-methylcarbamoyl fluoride in 10 ml of absolute acetonitrile. The reaction mixture is allowed to stir well at room temperature for 20 hours. Subsequently, the precipitated potassium salt is filtered off, and the filtrate is evaporated. Chromatography of the crude oily product on silica gel with ethyl acetate/toluene (1:3) as the eluent yields 5-oxo-2,2,4-trimethyl-3-thiazoline O-[N-(di-n-butylaminosulphenyl)-N-methylcarbamoyl]oxime, nD20 1.5200.