Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]1([CH:21](O)[CH2:22][CH:23]=[CH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:45][NH:46][S:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=[O:49])=[O:48]>C1COCC1.CCOCC.O>[CH3:45][N:46]([CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:22][CH:23]=[CH2:24])[S:47]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)(=[O:48])=[O:49]
Reactant: C=CCC(O)c1ccccc1
Reactant: CNS(=O)(=O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C=CCC(c1ccccc1)N(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.3 %

Procedure:
DIAD (9.0 mL, 45.9 mmol) was added dropwise over 10 min to a stirred solution of 1-phenyl-3-buten-1-ol (4.0 g, 27.0 mmol), PPh3 (10.6 g, 40.5 mmol) and N-methylphenylsulfonamide (6.0 g, 35.0 mmol) in THF (200 mL) under N2 and the resulting mixture was stirred at RT for 20 h. H2O (200 mL) and Et2O (200 mL) were added and separated. The organics were washed with brine (150 mL) and concentrated under reduced pressure while loading on to MgSO4. The mixture was then purified by column chromatography on silica eluting with 3% Et2O/iso-hexanes to yield the sulfonamide (6.45 g, 79%). 1H NMR (CDCl3, 360 MHz) δ 7.78 (2H, d, J=7.8 Hz), 7.53 (1H, t, J=7.8 Hz), 7.44 (2H, t, J=7.8 Hz), 7.30–7.18 (5H, m), 5.67–5.52 (1H, m), 5.20 (1H, t, J=7.8 Hz), 5.02 (1H, dd, J=17.1, 1.5 Hz), 4.93 (1H, dd, J=10.2, 1.3 Hz), 2.70 (1H, app. quintet, J=7.1 Hz), 2.65 (3H, s), 2.44 (1H, app. quintet, J=7.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]>CN(C)C1C=CN=CC=1.C(O)(C)(C)C>[C:5]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=1)([CH3:9])([CH3:6])[CH3:4]
Reactant: COc1cc(C(=O)O)ccc1O
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Product: COc1cc(C(=O)OC(C)(C)C)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 149.9 %

Procedure:
4-Hydroxy-3-methoxy-benzoic acid (1.0 g, 5.95 mmol), 1,3-dicyclohexycarbodiimide (1.5 g, 7.14 mmol) and 4dimethylaminopyridine (72.7 mg, 0.6 mmol) were mixed in t-butanol (10 mL) and stirred at room temperature for 4 hours. The reaction was filtered and purified by column chromatography to provide the title compound (1.0 g, 75%).
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N:16]1([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[C:31]([F:34])([F:33])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Product: CCCCCNC(=O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid pentylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(5-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (31% yield). m.p. 162-164° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.87, 7.24, 7.07, 6.99, 4.08-3.99, 3.90-3.66, 3.45, 3.35, 1.65-1.55, 1.37-1.30. 13C NMR (75 MHz, CDCl3) δ 166.1, 162.9, 160.0, 145.7, 129.7, 127.2, 116.9, 116.6, 115.0, 114.7, 112.6, 77.2, 46.4, 44.6, 44.4, 41.3, 39.4, 29.3, 29.1, 22.4, 14.0.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[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.[C:18]([O:22][CH3:23])(=[O:21])[C:19]#[CH:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:23][O:22][C:18](=[O:21])/[CH:19]=[CH:20]/[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1
Reactant: C#CC(=O)OC
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 115 °C
Yield: 90.6 %

Procedure:
4-(Adamantan-1-yl)-phenol (1.0 mg, 4.38 mmol) and methyl propiolate (737 mg, 0.74 ml, 8.76 mmol) were dissolved in 25 ml of toluene, to which Ph3P (1.15 g, 4.38 mmol) was added, followed by reflux at 115° C. for 3 hours. The reaction solution was concentrated and extracted with EtoAC and NaCl solution. The organic layer was dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc=50:1) to give the target compound as a white solid (1.24 g, yield: 90.6%).
Reaction SMILES: C[O:2][C:3]1[S:4][C:5]2[C:10]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[N:9][C:8]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:7][C:6]=2[N:25]=1.O>O1CCOCC1.Cl>[OH:14][CH2:13][C:12]([NH:11][C:10]1[C:5]2[S:4][C:3](=[O:2])[NH:25][C:6]=2[N:7]=[C:8]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:9]=1)([CH3:15])[CH3:16]
Reactant: COc1nc2nc(SCc3ccccc3)nc(NC(C)(C)CO)c2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(CO)Nc1nc(SCc2ccccc2)nc2[nH]c(=O)sc12
Temperature: 45 °C

Procedure:
To a solution of the product from example 1 step f) (0.21 g) in 1,4-dioxane (5 ml) was added water (0.1 ml) and concentrated hydrochloric acid (1 drop). The mixture heated at 45° C. for 3 hours then evaporated to dryness. Recrystallisation (acetonitrile) gave the title compound (0.110 g).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.CC(OC([NH:20][C:21]1[S:25][C:24]2[CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=[CH:29][C:23]=2[N:22]=1)=O)(C)C.ClCCl.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:30]([C:27]3[CH:28]=[CH:29][C:23]4[N:22]=[C:21]([NH2:20])[S:25][C:24]=4[CH:26]=3)=[O:31])[CH2:3]1)[CH2:9]2
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(C(=O)O)cc2s1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2ccc(C(=O)NC3C4CC5CC3CN(C5)C4)cc2s1
Reaction time: 8 h

Procedure:
The protected amide[6-(1-azatricyclo[3.3.1.13,7]dec-4-ylcarbamoyl)-benzothiazol-2-yl)-carbamic acid tert-butyl ester] was prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-N-Boc-amino-4-benzothiazole-6-carboxylic acid (Astatech) according to method A. The resulting material was dissolved in dichloromethane (4 mL), treated with dichloromethane-trifluoroacetic acid (4 mL, 1:1), and stirred overnight. After concentrating the reaction mixture under a nitrogen stream, the residue was triturated with ether, and washed with ether and ethyl acetate to afford the title compound; yield 20 mg, 0.03 mmol (43%): 1H NMR (300 MHz, methanol-d4) δ 2.05-2.31 (m, 5H), 2.46 (s, 2H), 3.41-3.61 (m, 4H), 3.83 (d, J=13 Hz, 2H), 4.27 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.88 (d, J=8 Hz, 1H), 8.23 (s, 1H); MS (DCI/NH3) m/z 329 (M+H)+; Anal. C17H20N4OS.2C2HF3O2: C, H, N.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:13]=1F)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:18][C:17]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:13]=2[C:14]([N+:19]([O-:21])=[O:20])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1c(F)ccc([N+](=O)[O-])c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)c2c1NCCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To an ice-cold solution of [3-(2,6-difluoro-3-nitrophenoxy)propyl]carbamic acid tert-butyl ester (296 mg, 0.8907 mmol) in DCM (15 mL) was added TFA (3 mL). The reaction mixture was stirred at RT for 2 h, then toluene was added and volatiles were removed under reduced pressure. The resulting residue was dissolved in acetonitrile (6 mL), 2M Na2CO3 (6 mL) was added and the mixture stirred at RT for 1.5 h. The reaction mixture was partitioned between EtOAc and brine, the organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, eluant 10-20% EtOAc in cyclohexane) affording the title compound as a red solid (158.4 mg, 84%). 1H NMR (CDCl3, 300 MHz): 8.08 (1H, bs), 7.87 (1H, dd, J=9.6, 5.6 Hz), 6.44 (1H, dd, J=9.8, 8.7 Hz), 4.40 (2H, t, J=6.6 Hz), 3.78-3.73 (2H, m), 2.29-2.20 (2H, m)
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[N:12][C:13]([Cl:27])=[CH:14][N:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41](Cl)=[O:42]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[N:12][C:13]([Cl:27])=[CH:14][N:15]=2)[N:10]=[C:9]1[CH:5]([NH:4][CH2:3][C:2]([NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([CH3:47])=[C:38]([F:37])[CH:39]=1)([CH3:29])[CH3:28])[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C(NCC(C)(C)N)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)(C)CNC(c2nc3nc(Cl)cnc3c(=O)n2Cc2ccccc2)C(C)C)cc1F

Procedure:
Formula 203 where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; Ra and Rb are Methyl; Rc is 3-Fluoro-4-methyl-phenyl-; W and Z are —N═; X and Y are —C═: To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-pteridin-4-one (133 mg, 0.32 mmol) in dichloromethane (3 mL) is added triethylamine (90 μL, 0.64 mmol), followed by 3-fluoro-4-methylbenzoyl chloride (51 μL, 0.35 mmol). The resultant solution is stirred at ambient temperature for 3 hours, quenched with saturated aqueous sodium bicarbonate (5 mL) and diluted with dichloromethane (5 mL). The aqueous layer is extracted with dichloromethane (5 mL) and the combined extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (10–20% ethyl acetate/hexanes) to give (±)-N-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-3-fluoro-4-methyl-benzamide.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1([C:35]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([S:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH2:5][CH2:4]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCC1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCN(S(=O)(=O)c2cccc3ccccc23)CC1)C1CCCCC1
Yield: 95.6 %

Procedure:
To a solution of 4-aminomethyl-1-(1-naphthylsulfonyl)piperidine (608 mg, 2.0 mmol) and triethylamine (303 mg, 3.0 mmol) in dichloromethane (30 mL) stirring at room temperature under argon, was added cyclohexanecarbonyl chloride (325 mg, 2.2 mmol) in a single portion. After 2 h the solvent was evaporated under vacuum, and the residue was slurried with diethyl ether and filtered. The filtrate was evaporated, and purification by column chromatography (silica gel, ethyl acetate in hexane) provided 4-(N-cyclohexylcarbonylaminomethyl)-1-(1-naphthylsulfonyl)piperidine (793 mg, 96% yield) as a gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[N:26][CH:27]=[CH:28][C:29]=1B(O)O)(=[O:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CCn1nc(Nc2cc(Br)cn(C)c2=O)cc1C
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CCn1nc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)cc1C
Temperature: 100 °C
Yield: 32.1 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 252a (200 mg, 0.64 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (309 mg, 0.64 mmol), PdCl2(dppf) (52.5 mg, 0.060 mmol), K3PO4 (333 mg, 1.29 mmol), sodium acetate (105 mg, 1.29 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 252b as a yellow solid (120 mg, 27.6%). MS-ESI: [M+H]+ 584.3
Reaction SMILES: CS[C:3]1[NH:8][C:7]2[CH:9]=[CH:10][N:11]=[CH:12][C:6]=2[S:5](=[O:14])(=[O:13])[N:4]=1.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:21][C:3]2[NH:8][C:7]3[CH:9]=[CH:10][N:11]=[CH:12][C:6]=3[S:5](=[O:14])(=[O:13])[N:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Product: O=S1(=O)N=C(NC2CCCCC2)Nc2ccncc21

Procedure:
A solution of 0.7 g of 3-methylthio-4H- pyrido[4,3-e][1,2,4]thiadiazine 1,1-dioxide in 7 cm3 of cyclohexylamine is heated at reflux for 4 hours. The reaction mixture is concentrated under partial vacuum and the residue is taken up in 10 cm3 of water and is slightly basified by addition of 10% sodium hydroxide solution. The aqueous phase is stirred with 25 cm3 of diethyl ether in order to extract a possible excess of cyclohexylamine. After separation by settling, the aqueous solution is adjusted to a pH of 7 and the white precipitate is collected on a filter and washed with water. It is recrystallized from hot water.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[OH-].[Na+].O>CC(N(C)C)=O.C1CCCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1
Reactant: BrCCCCBr
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: C1CCCCC1
Product: O=C1CCc2ccc(OCCCCBr)cc2N1
Temperature: 25 °C

Procedure:
1,4-dibromo butane (509 ml) was added to a stirred solution of 7-hydroxy-3,4-dihydrocarbostyril (100 gm) in dimethylacetamide (500 ml) at ambient temperature. The reaction mixture was heated at 36° to 40° C. Sodium hydroxide (33.1 gm) was added to the reaction mixture at the interval of 30 min (Complete the addition of sodium hydroxide in 9 equal fractions in 4.0 hours). The reaction mixture was cooled at ambient temperature and D.M Water was added to it. The reaction mixture was extracted with ethylacetate. Organic layer was separated and washed with 5% brine and finally dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure (10 mm) at 45° C. to obtain residue. To the residue cyclohexane (1000 ml) was added to give of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril.
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.CC(C)([O-:16])C.[K+].S1CCN=C1>C(O)(C)(C)C>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:16])[N:3]=1)[CH3:10]
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Reactant: CC(C)(C)[O-]
Agent: C1=NCCS1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN(C)Cc1nc(CO)cs1

Procedure:
The process of Example 5 was repeated using 5.0 g (0.24 mol) of 4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline, 25 ml of t-butylalcohol and 2.69 g (0.024 mol) of potassium t-butoxide. The HPLC assay set forth in Example 3 indicated that 90% of the thiazoline substrate had converted to the desired titled product.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].BrCCCCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.O=[CH:61][CH2:62][CH2:63][CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66]>CCOCC.CCCCCC>[C:65]([O:67][CH2:68][CH3:69])(=[O:66])[CH2:64][CH2:63][CH2:62]/[CH:61]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CCCC=O
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCCCCCCBr
Product: CCCCCC/C=C\CCCC(=O)OCC
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
Heptyltriphenylphosphonium bromide (16.8 g), prepared from 1-bromoheptane and triphenylphosphine analogously to undecyltriphenylphosphonium bromide as described in Example 2(2), is suspended in dry ether (300 ml) and the mixture is treated whilst stirring under nitrogen with 1.7M butyllithium in hexane (36 ml) from a syringe. The resulting bright red solution is cooled to 10° C. and treated dropwise with ethyl 5-oxopentanoate [5.5 g, prepared as described in Example 2 (1B)] in dry ether (37.5 ml). After 10 minutes, the reaction mixture is worked up by the procedure described in Example 2(2) to give ethyl (Z)-dodec-5-enoate as a yellow oil (8.6 g).
Reaction SMILES: [OH:1][NH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8](Cl)[CH:9]=[CH2:10].[OH-].[K+]>C(O)C>[CH2:10]([O:1][NH:2][C:3](=[O:4])[O:5][CH2:6][CH3:7])[CH:9]=[CH2:8]
Reactant: CCOC(=O)NO
Reactant: C=CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCONC(=O)OCC
Temperature: 80 °C

Procedure:
100 g of N-hydroxyurethane and 80.3 g of allyl chloride were added, at 20° C., to a solution of 53.8 g of potassium hydroxide in 750 ml of ethanol. The mixture was stirred and refluxed (80° C.) for 4 hours, then was cooled to 25° C. and filtered. The solvent was evaporated from the filtrate and the residue, an oil, was distilled, 51°-55° C., 0.2 Torr., to give ethyl (2-propenyloxy)carbamate, 3A, as a colorless oil.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C@H:7]3[C@H:10]4[C@H:20]([CH2:21][CH2:22][C@:5]23[CH3:6])[C@:18]2([CH3:19])[C:13]([CH2:14][C@@H:15]([CH3:23])[CH2:16][CH2:17]2)=[CH:12][CH2:11]4)[O:3]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[CH3:23][C@H:15]1[CH2:16][CH2:17][C@@:18]2([CH3:19])[C:13](=[CH:12][CH2:11][C@@H:10]3[C@@H:20]2[CH2:21][CH2:22][C@@:5]2([CH3:6])[C@H:7]3[CH2:8][CH2:9][C:4]2=[O:3])[CH2:14]1
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23OCCO3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1

Procedure:
The 3β-methylandrost-5-en-17-one 17-ethylene ketal (13) (2.20 g 6.7 mmol) was dissolved in acetone (100 ml). p-Toluenesulfonic acid (100 mg) and H2O (20 ml) were added and the solution was refluxed for 2 hours. The solution was evaporated, taken up in ether (30 ml), washed with saturated NaHCO3, H2O, and then dried over MgSO4. The solution was filtered and evaporated to give a colorless solid which was recrystallized from methanol to give 3β-methylandrost-5-en-17-one (14) as colorless plates, 1.17 g (61%) mp 148°-150° C.; IR(KBr) 3010, 2910, 1740, 1455, 1430, 1365 cm-1 ; 1H NMR (CDCl3) δ5.41 (brd, J=6Hz, 1H, H-6), 1.11 (s, 3H, C-19 Me), 0.99 (s, 3H, C-18 Me), 1.07 (d, 3H, C-3 Me); MS (m/e) 286 (M+, 58), 271 (51), 229 (31), 159 (36), 105 (72), 9- (95), 79 (89), 55 (9), 41 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[Cl:32])[CH2:28][CH:27]([NH:33][CH3:34])[CH2:26][CH2:25]2>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][C:31]([Cl:32])=[C:22]([Cl:21])[CH:23]=4)[CH2:28]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNC1CCc2cc(Cl)c(Cl)cc2C1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(Cl)c(Cl)cc3C1)CC2

Procedure:
The title compound is prepared from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 6,7-dichloro-2-methylamino-1,2,3,4-tetrahydronaphthalene analogously to Example 1. Mp.: 130° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)CCCc1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)CCCC1CCCCC1
Yield: 77 %

Procedure:
4-Phenylbutanoic acid prepared as described in Example 21, Part A was dissolved in glacial acetic acid (25 ml). Platinum oxide (0.1 g) was added and the solution was hydrogenated in the Paar shaker at up to 55 p.s.i. until hydrogen uptake ceased (6.5 hours). The catalyst was removed by filtration and the acetic acid was removed in vacuo. The product crystallized and was recrystallized from Et2O (20 ml) to give title compound (1.18 g, 77%), m.p. 85°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH2:21])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=2)[C:34](O)=[O:35])[N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH:21][C:34](=[O:35])[C:33]4[CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=[N:31][CH:32]=4)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN1CCC(CN)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CN1CCC(CNC(=O)c2cncc(-c3noc(C(F)(F)F)n3)c2)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Yield: 11 %

Procedure:
This compound was synthesized from (4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (17 mg, yield 11%). 1H NMR (400 MHz, MeOD) δ 9.36 (d, J=2.0 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H), 8.72 (t, J=2.0 Hz, 1H), 7.95-7.93 (d, J=8.5 Hz, 2H), 7.59 (br s, 1H), 7.44-7.42 (d, J=8.6 Hz, 2H), 3.73 (m, 2H), 3.50-3.49 (m, 2H), 2.87-2.83 (m, 7H), 2.21-2.16 (m, 2H). MS (ESI) m/z: Calculated for C25H22ClF3N6O2S: 562.12. found: 563.2 (M+H)+.