Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[N+:21]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[NH2:21])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])C1CCCCC1NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: NC1CCCCC1NC1CCN(Cc2ccccc2)CC1
Yield: 98.3 %

Procedure:
In this reference example, 1.0 g of 1-benzyl-4-(2-nitro-cyclohexylamino)-piperidine obtained in Reference Example 16 is dissolved in 25 ml of ethanol. Then, 1.0 g of a Raney-nickel catalyst is added thereto and the mixture is stirred at room temperature in the atmosphere of hydrogen under the atmospheric pressure. The stirring is ceased when the solution has absorbed the theoretical amount of hydrogen, and the reaction solution is filtered. The filtrate is concentrated. Consequently, 0.89 g of 1-benzyl-4-(2-aminocyclohexylamino)-piperidine is obtained as the residue.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([Cl:5])=[O:4].[CH3:16]C(CCCCCCCCCC)C(O)=O>>[CH3:1][C:2]([CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([Cl:5])=[O:4]
Reactant: CCCCCCCCCCC(C)C(=O)O
Reactant: CCCCCCCCCCC(C)C(=O)Cl
Product: CCCCCCCCCCC(C)(C)C(=O)Cl

Procedure:
In a similar manner to that described in Example 25 except for the use of 2-methyldodecanoyl chloride [synthesized by chlorinating 2-methyldodecanoic acid which was synthesized by the process described in Organic Synthesis, 4,616, by the method as described in B. D. Roth. et al., Journal of Medicinal Chemistry, 35, 1609-1617 (1992)] instead of 2,2-dimethyldodecanoyl chloride, 82.5 mg of the desired compound was obtained as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:27])[CH3:26])[N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Solvent: O
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Reaction time: 1 h

Procedure:
A 2.0 g (6.15 mmol) portion of the product of Example 26 was stirred with 10 ml of acetic anhydride at 25° C. for 3 hours then 50 ml of distilled water were added and the stirring was continued for one hour. The yellow precipitate formed was filtered, washed with 3×10 ml of distilled water and dried at 80°-100° C. to obtain 2.6 g of raw product. After recrystallization from 10 ml of ethanol 1.94 g (85.8%) of the aimed product were obtained, m.p.: 140°-142° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:16][C:3]1=2.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:8]([C:6]2[C:5](=[O:13])[C:4]3[CH:14]=[C:15]([CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:16][C:3]=3[N:2]([CH3:1])[CH:7]=2)=[O:9])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)NCc2ccc(F)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Yield: 50 %

Procedure:
A mixture of ethyl 7-methyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (0.300 g) from Preparation No. 4 and 4-fluorobenzylamine (1.02 mL) is stirred at 175° C. for 3 h. The reaction mixture is allowed to cool for several minutes and is then diluted with toluene (15 mL). The resulting off-white precipitate is filtered off and recrystallized from acetonitrile then ethanol to yield 0.184 g (50%) of the title compound as a white, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)=[CH:4][CH:3]=1.CC(O)=O>C(Cl)Cl.[Zn]>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccccc1Nc1ccc(Cl)cc1

Procedure:
To a solution of 2-(4-chloroanilino)-nitrobenzene (57.0 g) in CH2Cl2 (40 mL) was added AcOH (90 mL), then Zn powder (105 g) was added in small portions. After Zn powder was added, the color of the mixture became light green, filtered by suction, washed with CH2Cl2. The filtrate was concentrated to dryness. Water was added, filtered, and washed with water to give a brown solid. This solid was used directly in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1.[NH2:15][C:16]1[C:17]([F:29])=[CH:18][C:19]([F:28])=[C:20]([CH:27]=1)[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:24]1([NH:23][C:21](=[O:22])[C:20]2[CH:27]=[C:16]([NH:15][CH2:13][C:10]3[S:9][C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:12][CH:11]=3)[C:17]([F:29])=[CH:18][C:19]=2[F:28])[CH2:25][CH2:26]1
Reactant: Nc1cc(C(=O)NC2CC2)c(F)cc1F
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1)c1cc(NCc2cnc(Nc3ccccn3)s2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
A mixture of 2-[pyridin-2-ylamino]-thiazole-5-carbaldehyde (41.0 mg, 0.2 mmol) and 5-amino-N-cyclopropyl-2,4-difluorobenzamide (46.6 mg, 0.22 mmol) in TFA/DCM (1:1, 1 mL) was stirred at RT for 10 min and triethylsilane (0.1 mL) was added. The mixture was stirred for 1 h, then concentrated and the residue was neutralized with NaHCO3 solution and the precipitates occurred. The precipitates were collected, washed with water and dried. The solid was triturated with MeOH and filtered to afford the title compound as a grayish solid (38 mg, 47%). Small amount of solid was boiled in methanol, the mixture was cooled to RT and filtered to afford a white solid. MS m/z 402 (M+H)+. 1H NMR (DMSO-d6) δ 8.23 (d, 1H, J=4.0 Hz), 8.15 (s, 1 H), 7.65 (t, 1 H, J=7.15 Hz), 7.26 (s, 1 H), 7.16 (m, 1 H), 7.01 (d, 1 H, J=8.75 Hz), 6.95 (m, 1 H), 6.89 (t, 1 H, J=7.15 Hz), 6.12 (s 1 H), 4.43 (m, 2 H), 2.79 (m, 1 H), 0.69 (m, 2 H), 0.51 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5]([CH3:17])[CH:4]=1.C([Li])(CC)C.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=[O:26].Cl>O1CCCC1.O>[C:12]([O:11][C:10](=[O:16])[NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:17][CH:25]([OH:26])[C:24]([CH3:28])([CH3:27])[CH3:23])([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Reactant: CC(C)(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(NC(=O)OC(C)(C)C)c(CC(O)C(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (4-methoxy-2-methylphenyl)carbamate (475 mg) in tetrahydrofuran (7 mL) was added dropwise sec-butyllithium (1.04 mol/L hexane-cyclohexane solution, 4.3 mL) at −40° C. under an argon atmosphere, and the mixture was stirred for 15 minutes. Then a solution of trimethylacetaldehyde (0.287 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at −40° C. for 15 minutes and at room temperature for additional one hour. Water and μmol/L hydrochloric acid were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (234 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9]1)=[O:21]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CN1CCC(c2c[nH]c3ccncc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(c2cn(C(=O)c3c(Cl)cccc3Cl)c3ccncc23)CC1

Procedure:
from 3-(1-methyl-4-piperidinyl)-5-azaindole (20 mg, 0.094 mmol), 2,6-dichlorobenzoyl chloride (27 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[C:31]#[N:32])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:30])[C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[C:31]#[N:32])=[CH:13][CH:12]=2)=[O:10])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)C(F)c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C(F)C(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Yield: 103.7 %

Procedure:
A flask was charged with tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)-2-fluoroacetate (0.026 g), 0.5 ml of dichloromethane and 0.2 ml of TFA. The reaction was concentrated, and the residue was dissolved in a minimal amount of dichloromethane and placed under high vacuum to give a solid. The procedure was repeated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)-2-fluoroacetic acid (0.024 g) as a tan solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Si:20]([O:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH2:31]1)([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21]
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCCNC1
Product: CC(C)(C)[Si](C)(C)OCCC1CCCN(c2cnc(-c3ccccc3)c(-c3ccccc3)n2)C1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and (±)-3-[2-(tert-butyldimethylsilyloxy)ethyl]piperidine was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52](O)=[O:53])=[CH:40][CH:41]=2)[N:36]=1.Cl.[NH2:56][CH:57]1[C:66]2[CH:65]=[C:64]([O:67][CH2:68][C:69]3[CH:70]=[C:71]([CH:74]=[CH:75][CH:76]=3)[C:72]#[N:73])[CH:63]=[CH:62][C:61]=2[CH2:60][CH2:59][CH2:58]1>CN(C)C=O>[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([NH:56][CH:57]3[C:66]4[C:61](=[CH:62][CH:63]=[C:64]([O:67][CH2:68][C:69]5[CH:76]=[CH:75][CH:74]=[C:71]([C:72]#[N:73])[CH:70]=5)[CH:65]=4)[CH2:60][CH2:59][CH2:58]3)=[O:53])=[CH:40][CH:41]=2)[N:36]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: N#Cc1cccc(COc2ccc3c(c2)C(N)CCC3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC4CCCc5ccc(OCc6cccc(C#N)c6)cc54)ccc23)CC1
Reaction time: 2 h
Yield: 79.1 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 uL, 0.07 mmol) were added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) and 3-{[(8-amino-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]methyl}benzonitrile HCl salt (30 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) at r.t. The reaction was stirred for 2 h. and the product was purified without workup by RP-HPLC (pH=10) to afford the desired compound (0.013 g, 30%) as an amorphous white solid. 1H NMR (400 MHz, DMSO): δ8.84 (d, 1H), 7.77-7.6 (m, 5H), 7.46 (dd, 1H), 7.42 (m, 1H), 6.99 (d, 1H), 6.80 (dd, 1H), 6.74 (m, 1H), 6.36 (bs, 2H), 5.12 (m, 1H), 5.02 (s, 2H), 3.51 (bs, 4H), 3.27 (s, 4H), 2.62 (m, 2H), 2.17 (s, 3H), 1.88 (m, 2H), 1.70 (m, 2H). Analytical LCMS (M+H)+: m/z=548.1.
Reaction SMILES: O[CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2.O=S(Cl)Cl.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:13]1([C:10]2[CH:11]=[C:12]3[CH:2]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[C:3]4[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=[CH:19][C:4]=4[CH:5]=[CH:6][C:7]3=[N:8][CH:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(O)c1cc(-c3ccccc3)cnc1C=C2
Reactant: C1CCNC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(N1CCCC1)c1cc(-c3ccccc3)cnc1C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (40 mg, 0.11 mmol) in CH2Cl2 (2 mL) was added SOCl2 (30 uL, 0.41 mmol) at 0° C. The mixture was left to stir at 0° C. for 1 h and concentrated in vacuo. To the residue were added CH2Cl2 (2 mL) and pyrroldine (0.10 mL, 1.2 mmol) at 0° C. The mixture was allowed to warm to room temperature as the bath did, and left to stir overnight. The mixture was concentrated and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.83 (s, 1EI); 7.91 (s, 1H); 7.15-7.64 (m, 10H); 4.31 (br s, 1H); 3.02 (s, 3H); 2.09 (br s, 4H); 1.61 (br s, 4H). LRMS (APCI) calc'd for (C25H26N3O2S) [M+H]+, 432.2; found 432.1.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]([OH:13])[CH2:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.O>O1CCCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:13][CH:10]2[CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:12][CH2:11]2)=[O:31])=[CH:25][CH:24]=1
Reactant: OC1CN=C(c2ccccc2)OC1c1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
A solution of (5RS, 6SR)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.52 g) in anhydrous tetrahydrofuran (10 cc) is added at a temperature in the region of 20° C. to an oily suspension (50% by weight; 0.31 g), maintained under an argon atmosphere, of sodium hydride in anhydrous tetrahydrofuran (20 cc). The mixture is stirred for 30 minutes at the same temperature. A solution of 4-fluorophenyl isocyanate (0.9 g) in anhydrous tetrahydrofuran (10 cc) is then added dropwise and stirring is continued for 4 hours at a temperature in the region of 20° C. Distilled water (25 cc) is then added and the mixture is extracted with dichloromethane (3×50 cc). The organic phases are combined, washed with distilled water (3×20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: ethyl acetate/cyclohexane (3:7 by volume)], collecting 20-cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(4-fluorophenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (0.8 g), m.p. 158° C., is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:17]=[C:18]([C:22]2([CH3:28])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[CH3:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:17]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: CC1(c2cccc(O)c2)CCOCC1
Product: Cn1c(=O)ccc2cc(COc3cccc(C4(C)CCOCC4)c3)ccc21
Yield: 40 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-(3-hydroxyphenyl)-4-methyltetrahydropyran to give 4-methyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 40% yield, m.p. 107°-108° C.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:23]1([CH2:26][NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][NH:27][C:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[C:33]([C:2]3[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:34]=2)=[O:45])[CH2:25][CH2:24]1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.88 min, MH+ 493. NMR: δH [2H6]-DMSO 9.34, (1H, t), 9.16, (1H, d), 8.96, (1H, b), 8.62, (1H, t), 8.35, (1H, dd), 7.94, (1H, s), 7.85, (1H, d), 7.75, (1H, d), 7.43, (1H, d), 7.31, (1H, t), 7.21, (1H, s), 7.11, (2H, m), 4.52, (2H, d), 3.14, (2H, t), 2.99, (3H, s), 2.39, (3H, s), 1.03, (1H, m), 0.43, (2H, m), 0.23, (2H, m).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][N:4]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:25][C:24]([F:26])([F:27])[C:23]([C:20]1[CH:19]=[CH:18][C:17]([N:4]2[CH2:5][CH2:6][N:7]([S:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)(=[O:10])=[O:11])[CH2:8][C@@H:3]2[CH2:2][NH:1][CH:32]2[CH2:33][O:30][CH2:31]2)=[CH:22][CH:21]=1)([OH:29])[CH3:28]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN)cc1)C(F)(F)F
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNC2COC2)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.300 g, 0.667 mmol, Example 192, Step 1) in CH2Cl2 (5.0 mL) was added 3-oxetanone (0.050 mL, 0.67 mmol, Aldrich, St. Louis, Mo.), 4 molecular sieves (75 mg), and acetic acid (0.01 mL, 0.1 mmol). After stirred for 30 min, sodium triacetoxyborohydride (0.425 g, 2.01 mmol) was added and the reaction mixture was continued to stir at room temperature for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (2×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (80 g of silica gel, 2 to 5% 2M NH3 in MeOH/CH2Cl2) to afford 1,1,1-trifluoro-2-(4-((2S)-2-((3-oxetanylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.235 g) as a mixture of two isomers:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([N+:19]([O-])=O)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[H][H]>[Pt].C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:6]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([NH2:19])[C:4]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOc2ccccc2)c1C
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCOc2ccccc2)c1C
Reaction time: 3 h

Procedure:
Anhydrous toluene (100 ml), 5% platinum on carbon (Pt/C) (1.5 g), and 2,3-dimethyl-5-nitro-6-phenoxy-N-(2-phenoxyethyl)pyridin-4-amine (2.97 g) from Part C were placed in a Parr hydrogenation flask at a hydrogen pressure of 345 kPa for 4 hours with shaking. Additional 5% Pt/C (1.5 g) was added and the reaction was allowed to continue for 3 hours. The reaction mixture was filtered through a fluted filter paper and then through a folded No. 2 Whatman filter. The solvent was removed from the filtrate under reduced pressure and the resulting oil was used in the next step.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].S(C1C=CC(C)=CC=1)(O[CH2:13][C@@H:14]1[CH2:28][C@H:27]2[C@@H:17]([CH2:18][C:19]3[C:29]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]2=4)[NH:21][CH:20]=3)[N:16]([CH3:30])[CH2:15]1)(=O)=O>CN(C)C=O>[CH3:30][N:16]1[C@H:17]2[C@@H:27]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:29]=3[C:19]([CH2:18]2)=[CH:20][NH:21]4)[CH2:28][C@@H:14]([CH2:13][N:5]2[CH2:6][CH2:7][O:3][C:4]2=[O:8])[CH2:15]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C[C@H](CN2CCOC2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
0.5 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.0 g of oxazolidin-2-one and 15 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 1 hour. The solvent was distilled off under reduced pressure, and the residue (which was dissolved in dichloromethane and adsorbed on silica gel) was purified by silica gel column chromatography (eluted with ethyl acetate:isopropyl alcohol=1:1 by volume). The product was recrystallized from isopropyl alcohol to obtain 1.3 g of the titled compound as colorless needles having a melting point higher than 240° C. (with decomposition).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH:15]([CH3:20])[CH2:16][C:17](O)=[O:18])=[CH:10][CH:9]=2)[CH:2]=1.O.[NH2:23][NH2:24].[ClH:25]>COCCO>[ClH:25].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]([CH3:20])[CH2:16][C:17](=[O:18])[NH:23][N:24]=3)=[CH:10][CH:9]=2)[CH:2]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(Cc2cccnc2)cc1
Agent: Cl
Solvent: O
Solvent: COCCO
Product: CC1CC(=O)NN=C1c1ccc(Cc2cccnc2)cc1

Procedure:
7.1 g (0.025 mole) of 4-(4-(3-pyridylmethyl)-phenyl)-4-oxo-3-methyl-butyric acid and 1.5 ml (0.03 mole) of hydrazine hydrate are stirred in 30 ml of ethylene glycol monomethyl ether at 100° C. for 1 hour. After addition of ethanolic hydrochloric acid, the product is filtered off with suction and recrystallised from 96% strength ethanol.