Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:26]1[N:27]=[C:28]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[N:33]2)[O:29][CH:30]=1)[C:10]([C:12]1[N:13]=[C:14]([CH:23]2[CH2:25][CH2:24]2)[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:37]([C:34]1[CH:35]=[CH:36][N:32]([CH2:31][C:28]2[O:29][CH:30]=[C:26]([NH:9][C:10]([C:12]3[N:13]=[C:14]([CH:23]4[CH2:24][CH2:25]4)[S:15][C:16]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:11])[N:27]=2)[N:33]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)c1ccn(Cc2nc(N(C(=O)OC(C)(C)C)C(=O)c3nc(C4CC4)sc3-c3ccccc3)co2)n1
Agent: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccn(Cc2nc(NC(=O)c3nc(C4CC4)sc3-c3ccccc3)co2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(3-acetyl-pyrazol-1-ylmethyl)-oxazol-4-yl]-(2-cyclopropyl-5-phenyl-thiazole-4-carbonyl)-carbamic acid tert-butyl ester (13 mg, 0.02 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.08 mL, 1.00 mmol). After stirring at rt for 16 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1→3:1 hept:EA) gave the title compound as a white solid. TLC: rf (1:1 hept-EA)=0.34. LC-MS-conditions 02: tR=1.08 min, [M+H]+=433.89.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Br.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20]
Reactant: CN(C)CCN
Reactant: CC1(C)CC(n2ncc(Br)c(Br)c2=O)CC(C)(C)C1
Product: CN(C)CCNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1Br

Procedure:
4-Bromo-5-(2-dimethylaminoethyl)amino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one was prepared from 4,5-Dibromo-2-(3,3,5,5-tetramethyl cyclohexyl)pyridazin-3-one in a similar manner using 2-Dimethylaminoethyl amine (4 equivalents). 1H NMR (300 MHz CDCl3) 7.51 (s, 1H), 5.53 (m, 1H), 5.33 (m, 1H), 3.34 (m, 2H), 2.60 (m, 2H), 2.3 (s, 6H), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:21])[CH:7]=1.[H-].[Na+].I[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:25])=[O:19])=[CH:16][CH:17]=2)=[C:8]([CH3:21])[CH:7]=1
Reactant: Cc1cc(C2=NCCO2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(C3=NCCO3)cc2C)cc1
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
4'-(4,5-Dihydrooxazol-2-yl)-2'-methylbiphenyl-4-carboxylic acid (D113) (0.92 g, 3.3 mmol) was stirred under Ar in dry DMF (20 ml), and sodium hydride (80% in mineral oil, 0.15 g, 5.0 mmol) was added. This mixture was stirred for 30 min, and then treated with iodomethane (0.22 ml, 3.5 mmol). After a further 15 min, the mixture was diluted with ethyl acetate (200 ml), washed with water and brine, dried (Na2SO4) and evaporated. The crude product was purified by chromatography on silica gel, eluting with 0-2% methanol/dichloromethane. This gave the title compound (0.15 g, 15%) as a white solid.
Reaction SMILES: C([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH2:18][O:19][C:20](=[O:23])[C:21]=3[CH3:22])[CH2:13][CH2:12]2)[CH:10]([OH:26])[CH2:9]1)C1C=CC=CC=1>CO.[Pd].CC(O)=O>[OH:26][CH:10]1[CH2:9][NH:8][CH2:25][CH2:24][C:11]21[C:15](=[O:16])[N:14]([C:17]1[CH2:18][O:19][C:20](=[O:23])[C:21]=1[CH3:22])[CH2:13][CH2:12]2
Reactant: CC1=C(N2CCC3(CCN(Cc4ccccc4)CC3O)C2=O)COC1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC1=C(N2CCC3(CCNCC3O)C2=O)COC1=O
Reaction time: 16 h

Procedure:
To a solution of 8-benzyl-6-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (150 mg, 0.42 mmol) in MeOH (2 mL) was added palladium on carbon (45 mg, 0.42 mmol) and a few drops of HOAc. The mixture was allowed to stir under an atmosphere of hydrogen for 16 hours. LC indicated complete reaction. The catalyst was filtered off, and the crude material was used without further purification. LCMS: m/z 267 (M+H)+.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH:5]([OH:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:3]#[C:4][CH:5]([OH:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(O)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(O)CCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 1-trimethylsilyl-1-decyn-3-ol (2.07 g, 9.13 mmol) in tetrahydrofuran (11 mL) and place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between methylene chloride and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C@:8]2([CH3:22])[CH2:14][C@@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][CH2:11][C:10]([NH2:21])=[N:9]2)[CH:7]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:21][C:10]1[CH2:11][O:12][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:23])([CH3:22])[N:9]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](c2ccccc2)OCC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)C[C@@H](c2ccccc2)OCC(N)=N1

Procedure:
The compound was prepared in an analogous manner as described for the preparation of the amides Ia from (5S ,7S)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-7-phenyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (intermediate A10G) and 5-fluoropyridine-2-carboxylic acid. The title compound was obtained as a white solid. MS (ISP): m/z=437.3 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[CH:30]=2)[C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCc1cccc(Br)c1
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2cccc(Br)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (5.5 g) synthesized in Example 265-1 and 1-bromo-3-(bromomethyl)benzene (4.04 g) were dissolved in N,N-dimethylformamide (55 mL), potassium tert-butoxide (1.82 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (6.3 g) as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:23]
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 14.5 g of 3-(2-quinolinylmethyloxy)benzyl alcohol in 150 ml of CHCl3 is added dropwise 7.5 ml of thionyl chloride during 10 min. The reaction mixture is stirred for 4 hours at room temperature, and then washed with NaHCO3 solution. The organic solution is separated, dried, and evaporated to give 3-(2-quinolinylmethyloxy)benzyl chloride which is used without further purification in the next step.
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].[CH2:5]([S:11][CH2:12][CH2:13][CH2:14]Cl)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:5]([S:11][CH2:12][CH2:13][CH2:14][N:2]=[C:1]=[S:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCSCCCCl
Reactant: N#C[S-]
Agent: [K+]
Product: CCCCCCSCCCN=C=S

Procedure:
n-C6H13SCH2CH2CH2Cl is added to a solution of KSCN in refluxing N,N-dimethylformamide at about 155° C. in an amount sufficient to provide a n-C6H13SCH2CH2Cl:KSCN molar ratio of about 1:1. Upon completion of the addition of n-C6H13SCH2CH2CH2Cl, the reaction mixture is refluxed an additional 0.5 hours. The amount of n-C6H13SCH2CH2CH2NCS formed was measured by gas chromatography/mass spectrometry.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1)CCC.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>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].C1(C)C=CC=CC=1>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([C:6]1[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)=[O:32]
Reactant: O=C(Cl)CCCCBr
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC)c(OC)c(OC)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)CCCCBr)cc(OC)c1OC

Procedure:
A solution of 8.5 g of the compound obtained in Step A, 3.2 ml of 5-bromopentanoyl chloride, 0.3 g of Pd2(dba)3 and 250 ml of toluene is refluxed for 6 hours, and then cooled and evaporated in vacuo. The residue is purified by chromatography over silica gel eluted with dichloromethane, enabling the expected product to be isolated.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[C:13]([Br:17])[C:14]([Br:16])=[CH:15][C:10]=2[NH:9][C:8](=[O:18])[C:7]2[CH:19]=[CH:20][CH:21]=[N:22][C:6]1=2)=[O:4].[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[Br:16][C:14]1[C:13]([Br:17])=[CH:12][C:11]2[N:5]([C:3](=[O:4])[CH2:2][N:29]3[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]3)[C:6]3[N:22]=[CH:21][CH:20]=[CH:19][C:7]=3[C:8](=[O:18])[NH:9][C:10]=2[CH:15]=1
Reactant: OCCN1CCNCC1
Reactant: O=C1Nc2cc(Br)c(Br)cc2N(C(=O)CCl)c2ncccc21
Solvent: CCO
Product: O=C1Nc2cc(Br)c(Br)cc2N(C(=O)CN2CCN(CCO)CC2)c2ncccc21

Procedure:
11-Chloroacetyl-8,9-dibromo-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (0.05 mole) and 0.13 mole 4-(2-hydroxyethyl)piperazine, dissolved in 800 ml. ethanol are heated to reflux for a period of 20 hours. The hot solution is then filtered, the filtrate evaporated in vacuo and the remaining residue recrystallized from 2-propanol to give 8,9-dibromo-6,11-dihydro-11-[[4-(2- hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)#[N:7].[OH-].[K+]>C(O)C.O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:2][CH2:3][CH2:4][OH:5])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)#[N:7]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(OCCCO)cc2)cc1
Temperature: 25 °C

Procedure:
3-Bromo-1-propanol (5.6 g, 0.04 mol) and 4-cyano-4'-hydroxybiphenyl (6.0 g, 0.02 mol) were dissolved in ethanol (300 ml) and agitated at room temperature. To this solution was gradually dropwise added a solution of KOH (10 g) dissolved in water (20 ml), over 30 minutes, followed by stirring for 40 hours, distilling off about 200 ml of ethanol under reduced pressure, adding water (500 ml) to deposit solids, adding toluene (300 ml) to the mixture system, filtering off insoluble matter, washing the toluene solution twice with 2N-NaOH, then three times with water, drying over anhydrous sodium sulfate, distilling off toluene, and recrystallizing the resulting crystals from methanol to obtain 4-cyano-4'-(3-hydroxypropoxy)biphenyl. Yield: 2 g (28%). C-N: 109.0°-110.7° C. N-I: 113.6° C.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]1[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:10]=1[Cl:17])SC)#[N:2].[CH3:18][NH2:19]>C(O)C>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][C:9]1[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:10]=1[Cl:17])#[N:2]
Reactant: CSC(=NCc1[nH]c(=O)[nH]c(=O)c1Cl)NC#N
Reactant: CN
Solvent: CCO
Product: CNC(=NCc1[nH]c(=O)[nH]c(=O)c1Cl)NC#N
Temperature: 50 °C
Yield: 96 %

Procedure:
Next, 150 mg of the N-cyano-N'-(5-chlorouracil-6-ylmethyl)-S-methylisothiourea were suspended in ethanol (3 ml), followed by the addition of 2 ml of a 30% solution of methylamine in ethanol. The resulting mixture was heated at 50° C. for 3.5 hours under stirring. After an insoluble matter was filtered off, the filtrate was allowed to cool back to room temperature. A precipitate from the filtrate was collected by filtration, whereby 12 mg of the title compound were obtained (yield: 96%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:46])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[C:36]([CH2:37][O:38]C3CCCCO3)=[CH:35][N:34]=[N:33]2)[CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:18]([F:20])([F:21])[F:19])=[CH:10][C:9]3[NH:22][C:23](=[O:46])[CH2:24][C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[C:36]([CH2:37][OH:38])=[CH:35][N:34]=[N:33]5)[CH:27]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-azetidin-1-yl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M54) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (182 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl.CO>[C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2=[O:28])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2=O

Procedure:
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine (10 g) in dichloromethane (125 cc) there was rapidly added a solution of 85% m-chloroperoxybenzoic acid (6.61 g) in methanol (125 ml). At first the solids dissolved, then after a few minutes a new solid separated out of solution. After 1 and 1/2 hours the mixture was filtered and the solid washed with dichloromethane. The title compound was thus obtained pure (8.76 g), m.p. 179°-181° C.
Reaction SMILES: [C:1](Br)#[C:2][CH3:3].[Na].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[H-].[Na+]>O.CN(C)C=O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][CH2:14][N:15]([CH2:3][C:2]#[CH:1])[CH2:16][CH2:17]1
Reactant: CC#CBr
Reactant: c1ccc(N2CCNCC2)nc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1CCN(c2ccccn2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Propynylbromide (11.9 g.) was added to the sodium salt of N-(2-pyridyl)piperazine prepared from 16.3 g. of N-(2-pyridyl)piperazine and 4.8 g. of sodium hydride/50% mineral oil dispersion in 50 ml. of dry dimethylformamide. The mixture was stirred at 50° C. for 3 hours and then carefully poured into 3 volumes of cold water. This mixture was extracted with several portions of either and the combined ether extracts were washed twice with 10% aqueous hydrochloric acid. The acidic extract was made strongly alkaline by adding 40% aqueous sodium hydroxide under cooling. The mixture was then extracted several times with ether and the combined extracts were dried over magnesium sulfate. The latter was then removed by filtration, and the filtrate was evaporated to produce a brown oil. Distillation under reduced pressure gave N'-(2-pyridyl)-N-(2-propynyl)piperazine, b.p. 153°-4° C./3.5 mm, as a yellow oil which showed the expected NMR and IR spectra.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[C@@H:13]([Cl:28])[CH2:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C@@H:13]([Cl:28])[CH2:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 54.3 %

Procedure:
2.0 g of 21-acetoxy-6α-chloro-11β-hydroxy-16α-methyl-4-pregnene-3,20-dione is dissolved in 100 ml of dioxane; 3 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added thereto and the mixture heated for 24 hours to boiling. After cooling, the mixture is vacuum-filtered from the undissolved matter, washed with dichloromethane, and concentrated under vacuum. The crude product is chromatographed on silica gel. With 37-46% acetone-hexane, after recrystallization from acetone-diisopropyl ether, 1.08 g of 21-acetoxy-6α-chloro-11βhydroxy-16α-methyl-1,4-pregnadiene-3,20-dione is obtained, m.p. 208.5° C. [α]D25 =+90° (chloroform). UV: ε243 =15,700 (methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([Mg]Br)[CH:11]=[CH2:12].C1COCC1>>[CH3:12][C:11](=[CH2:10])[CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)[OH:6]
Reactant: C=CC[Mg]Br
Reactant: Cc1cccc(C=O)c1
Solvent: C1CCOC1
Product: C=C(C)C(O)c1cccc(C)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
3-Methylbenzaldehyde (Aldrich 97%, 62 g, 0.5 mol) was added drop-wise over 1 hour to a commercial solution of 2-propenyl magnesium bromide in THF (Aldrich 0.5 N, 800 ml, 0.4 mol), at −78° C. under nitrogen. The cooling bath was removed and the reaction stirred for 5 hours, before being cooled to 0° C. A saturated aqueous solution of ammonium chloride (300 ml) was added drop-wise at such a rate that the temperature was kept below 20° C. Diethyl ether (600 ml) was then added and the reaction was transferred to a separating funnel. After shaking vigorously, the phases were separated. The organic phase was washed with water and saturated aqueous sodium bicarbonate. Each aqueous phase was re-extracted with diethyl ether. The organic fractions were combined and dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with diethyl ether and the solvents were removed under vacuum. The product was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 5:1) followed by distillation through a 20-cm Widmer column. 33 g of the desired product were obtained (yield=51%). B.P.=55° C./0.009 mbar
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=2[Cl:23])[C:19](=[O:24])[NH:18][CH:17]=[CH:16]3)[CH2:8][CH2:7]1)C.[OH-].[Na+]>CO>[Cl:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][NH:18][C:19]2=[O:24])=[CH:14][C:13]=1[O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:25])=[O:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CN1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
1.56 g (4.27 mmol) [4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-acetic acid ethyl ester (41) were dissolved in 20 mL of methanol and 20 ml of 2N NaOH were added. After stirring for 1 h at room temperature, the solvent was removed i. vac. and the residue was dissolved in water. The aqueous solution was neutralized by adding 2 N HCl. Filtration of the precipitate and drying gave 856 mg of the title compound. Rt=0.82 min (Method B). Detected mass: 337.1 (M+H+).
Reaction SMILES: CC(C)N=C=NC(C)C.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1.[C:23]1([C:29]#[C:30][C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[CH3:10][N:11]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1)[C:31](=[O:32])[C:30]#[C:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: CNC1CCN(c2nccs2)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: CN(C(=O)C#Cc1ccccc1)C1CCN(c2nccs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
685 μl (4.38 mmol) DIC was added to a solution of 785 mg (4.00 mmol) N-methyl-1-(thiazol-2-yl)piperidin-4-amine and 640 mg (4.38 mmol) 3-phenyl-propiolic acid in MeCN (40 ml) and the reaction solution was stirred for 3 h at RT. Subsequently, concentration took place in vacuo and the residue was taken up by chloroform, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. 421 mg (1.30 mmol, 32%) (N-methyl-3-phenyl-N-(1-(thiazol-2-yl)piperidin-4-yl)propiolamide was obtained by CC (SiO2, 1.DCE 2.Chloroform). MS [MH+] 326.1
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[C:20]3[C:21]4([CH2:24][O:25][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23][CH2:22]4)=[CH:12][CH:13]=1)=[O:6])([CH3:4])[NH2:3].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:27](=[O:29])[N:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[C:20]4[C:21]5([CH2:24][O:25][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH2:23][CH2:22]5)=[CH:12][CH:13]=2)[C:5]1=[O:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 139.9 %

Procedure:
To a solution of 2-methyl-N1-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]alaninamide (Intermediate 91, 34 mg) in dry dichloromethane (6 mL) TEA (0.070 mL, 0.501 mmol) was added and the mixture was cooled to 0° C. A solution of triphosgene (13.38 mg, 0.045 mmol) in dry dichloromethane (2 mL) was slowly added and the reaction mixture was stirred for 1 hour at the same temperature. The reaction was quenched with water (3 ml) and two phases were separated. The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column SNAP and cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 as eluents affording the title as a white solid (23 mg).