Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[CH3:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:55][CH2:56][C:57]1[CH:58]=[CH:59][C:60]([F:64])=[C:61]([OH:63])[CH:62]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:55][CH2:56][C:57]2[CH:58]=[CH:59][C:60]([F:64])=[C:61]([OH:63])[CH:62]=2)=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: NCc1ccc(F)c(O)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
To a solution of 3-Methyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (220 mg, 1.10 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.46 mL, 3.30 mmol), HBTU (0.63 g, 1.65 mmol), HOBT (178 mg, 1.32 mmol), and 5-Aminomethyl-2-fluoro-phenol (187 mg, 1.32 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 60-80% EtOAc in hexane to afford the desired product (0.3472 g, 98% yield).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH:16]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH:16]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:3][CH:4]=1)=[O:7]
Reactant: CCOC(=O)C1CSCCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CCOC(=O)C1CSCCN1c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.4 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (1.1 g, 5.10 mmol) was added to ethyl thiomorpholine-3-carboxylate (2.0 g, 11.41 mmol) neat while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one hour and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified via column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield the title compound (1.71 g, 95%) as a yellow oil. [M+H] calc'd for C15H18N2O6S, 356. found, 356.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH:10]=[C:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:7]=1[CH3:8].C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:19][C:17]1[C:4]2[C:5](=[N:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=2)[N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CNc1ccc(I)c(C)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2nc(C)c(I)cc2c1O
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of diethyl 2-{[(5-iodo-6-methyl-2-pyridinyl)amino]methylene}malonate Prep 3(1.09 g) in 20 mL diphenyl ether is heated at 250° C. for 2 h with removal of ethanol via a Dean-Stark trap. The reaction is cooled to room temperature. Hexanes (15 mL) are added and the solid is filtered, washed thoroughly with hexanes, and dried. The crude solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (2L)) affords the product as a yellow-green solid (0.50 g, 52%). Physical characteristics are as follows: m.p. 275-277° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 12.80, 8.72, 8.47, 4.21, 2.74, 1.27; IR (drift) 2981, 1718, 1606, 1524, 1407, 1376, 1356, 1319, 1291, 1244, 1192, 1185, 1109, 809, 623 cm−1; MS (ESI) m/z 358.9 (M+H)+, 356.9 (M−H)−; Anal. Calcd for C12H11IN2O3: C, 40.24; H, 3.10; N, 7.82; Found: C, 40.15; H, 3.05; N, 7.81.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].[Br:27]Br>CCO>[Br:27][C:8]1[CH:7]=[C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:25])[F:26])[CH:11]=[CH:10][C:9]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17]1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(C)(O)C(F)(F)F)cc2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(C)(O)C(F)(F)F)cc2Br)CC1
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
A 500 mL round-bottomed flask was charged with tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.61 g, 23.0 mmol) and 100 mL of EtOH. To this was added bromine (1.30 mL, 25.3 mmol). After 15 min, the reaction was concentrated and purified via column chromatography (120 g of silica, 0 to 40% EtOAc in hexanes) to give tert-butyl 4-(2-bromo-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (6.50 g) as a tan foam.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)=[S:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Product: S=C(Nc1ccc(Cl)c(Cl)c1)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate is treated with 3,4-dichlorophenyl isothiocyanate in the manner described in Example 10 to obtain the title compound as the hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[NH2:18])=[CH:6]/[C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH3:2]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:5]1[NH:18][CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][C:7](=[O:17])[CH:6]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)/C(N)=C/C(=O)/C=C/c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C1=CC(=O)CC(c2ccc(Cl)cc2)N1

Procedure:
Using the procedure of Example 5, (2Z,5E)-2-amino-6-(4-chlorophenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (8; 47 g, 0.168 mol) in 1,4-dioxane (470 mL) in a 2 liter Parr reactor gave, following purification by silica gel chromatography eluting with 40% EtOAc/hexanes, 6-(4-chlorophenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid ethyl ester (12; 25 g, 49%, 99% pure by HPLC) as an off-white solid: mp 93-94° C.; 1H NMR (400 MHz, CDCl3) δ 7.36 (q, J=8.6 Hz, 4H), 5.82 (s, 1H), 5.72 (br s, 1H), 4.74 (dd, J=14.2, 5.0 Hz, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.68 (dd, J=16.3, 14.2 Hz, 1H), 2.58 (dd, J=16.4, 5.0 Hz, 1H), 1.36 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H14ClNO3, 279.067. found, 279.066.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CC1NC=NC=1CSC[CH2:21][NH:22][C:23]1[C:27](OC)=[N:26][S:25](=[O:30])[N:24]=1.CN>>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:27]1[C:23]([NH:22][CH3:21])=[N:24][S:25](=[O:30])[N:26]=1
Reactant: COC1=NS(=O)N=C1NCCSCc1nc[nH]c1C
Reactant: Cc1[nH]cnc1CSCCN
Agent: CN
Product: CNC1=NS(=O)N=C1NCCSCc1nc[nH]c1C

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide obtained from the above Step A is reacted with an equimolar amount of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine and the resulting 3-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with an excess of methylamine, and the title compound is thereby produced.
Reaction SMILES: CO[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[CH:4]=1.P(Cl)(Cl)([Cl:13])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[Cl:13][C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[CH:4]=1
Reactant: COc1cnn(C)c(=O)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1ncc(Cl)cc1=O
Temperature: 110 °C
Yield: 58.4 %

Procedure:
A mixture of 1.50 g (10.70 mmol) of 5-methoxy-2-methyl-2H-pyridazin-3-one and 7.8 ml (13.1 g, 85.6 mmol) of phosphorus oxychloride was heated at 110° C. for 2 h. After allowing to cool to room temperature, the mixture was poured into 100 ml of ice/water with vigourous stirring. After neutralization by addition of saturated sodium carbonate solution, the compound was worked up with methylene chloride/water, dried over magnesium sulfate and concentrated in vaccuo. The crude material was purified by flash chromatography on silicagel using a 80:20 mixture of ethyl acetate and heptane as eluant to yield 904 mg (6.25 mmol, 58%) of the title compound as a crystalline white solid, MS: 141.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:41]([C:43]1[C:47]([O:48][C:49]2[CH:50]=[C:51]([CH:54]=[C:55]([F:57])[CH:56]=2)[C:52]#[N:53])=[C:46]([CH2:58][CH2:59]O)[NH:45][N:44]=1)[CH3:42]>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:42][CH2:41][C:43]2[NH:44][N:45]=[C:46]([CH2:58][CH3:59])[C:47]=2[O:48][C:49]2[CH:50]=[C:51]([CH:54]=[C:55]([F:57])[CH:56]=2)[C:52]#[N:53])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCc1n[nH]c(CCO)c1Oc1cc(F)cc(C#N)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1n[nH]c(CCOc2ccc(C#N)cc2)c1Oc1cc(F)cc(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
4-Hydroxy-benzonitrile (49 mg, 0.41 mmol), triphenylphosphine (106 mg, 0.41 mmol) and diethylazodicarboxylate (65 μl, 0.41 mmol) were added sequentially to a solution of the alcohol from Example 148 (74 mg, 0.27 mmol) in tetrahydrofuran (2 ml) under nitrogen at 0° C. The reaction was allowed to warm to room temperature and was stirred for 18 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with toluene:ethyl acetate (75:25, by volume) to provide the title compound (50 mg) as a yellow oil.
Reaction SMILES: [N:1]1([CH2:7][CH:8]([OH:10])[CH3:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C1(C)C=CC=CC=1>[O:23]=[C:19]([CH3:18])[CH2:20][C:21]([O:10][CH:8]([CH3:9])[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:22]
Reactant: CC(O)CN1CCOCC1
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC(C)CN1CCOCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.0 g (34.4 mmol) 1-(4-Morpholinyl)-2-propanol and 35 mg (0.34 mmol) triethylamine are dissolved in 40 ml toluene. At 90° C., 3.76 g (44.77 mmol) diketene are added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling down to room temperature, the mixture is poured into ice-water. The phases are separated and the water phase is extracted two times with toluene. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:22]>O1CCCC1.O.C(#N)C>[Li+:22].[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH:4]([CH3:19])[C:3]([O-:20])=[O:2])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)CN1CCN(c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(CN1CCN(c2ccc(Cl)cc2)CC1)C(=O)[O-]
Yield: 41.9 %

Procedure:
3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-methyl-propionic acid methyl ester (586 mg; 1.98 mmol, prepared in accordance with Example 59) and lithium hydroxide (60 mg; 2.50 mmol) are suspended in a mixture of tetrahydrofuran (4 mL) and water (1 mL). The resulting mixture is irradiated in a mono-mode microwave oven for 50 minutes at 100° C. The mixture is then diluted with acetonitrile until precipitation occurs. The solid formed is then filtered and dried under high vacuum to afford the desired product (238 mg; 0.83 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][C@H:20]1[OH:28]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C@:19]2([NH2:18])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@H:20]2[OH:28])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)[C@]1(N)c2ccccc2C[C@H]1O

Procedure:
Following the General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-(S)-amino-2-(R)-indanol, the title compound was prepared.
Reaction SMILES: [ClH:1].[CH:2]1([N:11]2[CH2:27][CH2:26][C:14]3([N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][C:15]3=[O:25])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:28]I>>[ClH:1].[CH:2]1([N:11]2[CH2:27][CH2:26][C:14]3([N:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][N:16]([CH3:28])[C:15]3=[O:25])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCc3ccccc31)CC2
Reactant: CI
Agent: Cl
Product: CN1CN(c2ccccc2)C2(CCN(C3CCc4ccccc43)CC2)C1=O

Procedure:
The title compound, m.p. 200-203° C. and MS: m/e=362.2 (M+H+) was prepared in accordance with the general method of example 4 from (RS)-8-indan-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (1:1) and methyl iodide.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[C:11]([Cu])#[N:12]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([C:11]#[N:12])=[CH:3]1
Reactant: N#C[Cu]
Reactant: Brc1csc2ncccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1csc2ncccc12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3-bromothieno[2,3-b]pyridine (J-3) (107 mg, 0.5 mmol) and CuCN (60 mg, 0.67 mmol) in anhydrous DMF (4 mL) was added Pd(PPh3)4 (57 mg, 0.05 mmol). The reaction was degassed with nitrogen and stirred at 120° C. for 5 h. Then the cooled mixture was concentrated and purified by chromatography to afford the title compound. MS (m/z): 161 (M+1)+.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](OC(C)=C)(=[O:12])[CH3:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[C:10]([O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: C=C(C)OC(C)=O
Reactant: O=C1CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OC1=CCCCCCC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
In the presence of 0.6 g of para-toluenesulfonic acid, 50 g (0.4 mol) of cyclooctanone and 100 ml (0.9 mol) of isopropenyl acetate were refluxed for 11 hours. The reaction mixture was cooled, stirred with 0.6 g of anhydrous sodium carbonate at room temperature for one hour, left standing overnight, and filtered. The filtrate was distilled under reduced pressure to afford 60 g (91% in yield) of 1-cyclooctenyl acetate having a boiling point of 71° to 73° C./3 mmHg.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7].O.[BH4-].[Na+].C(O)(=O)C(C(C(O)=O)O)O>CCOCC.C(O)C>[CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]=[CH:5][CH:6]([OH:8])[CH3:7]
Reactant: CC(=O)C=CCC(C)CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(O)C=CCC(C)CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 494.1 %

Procedure:
58, 9 g of 6,8-dimethyl-3-nonen-2-one, 25 ml of water and 70 ml of ethanol are added to a 250 ml round flask which is provided with a stirrer and a thermometer. 8 g of sodium borohydride are added slowly while maintaining the temperature below 25° C. by cooling with a cold water bath. The mixture is now stirred at 25° C. for 3 hours. 50 ml of a saturated solution of tartaric acid and 100 ml of ether are added to the reaction mixture. The organic layer is then washed with brine until neutral. The solvent is evaporated. There are obtained 58 g of crude product, distillation of which yields 45 g (76,2%) of 6,8-dimethyl-3-nonen-2-ol of boiling point 88°-90° C./5 mm; nD20 =1,4435; d420 =0,8330.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14]CC)=O)=[CH:6]2.[CH3:18][C:19]([O-])(C)C.[K+].C1COCC1.C(OC)(=O)C=C.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:18][CH2:19][C:12](=[O:14])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:17]
Reactant: CCOC(=O)c1cc2c(C)c(OC)ccc2[nH]1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CC(=O)OC
Solvent: Cc1ccccc1
Product: COc1ccc2c(cc3n2CCC3=O)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of ethyl 5-methoxy-4-methyl-1H-indole-2-carboxylate (712 mg, 3.05 mmol) in toluene (10 mL) was added a 1 M solution of KOtBu in THF (3.97 mL, 3.97 mmol). The reaction mixture was stirred at room temperature for 5 min, methyl acrylate (825 μL, 9.15 mmol) was added. The reaction was stirred at reflux overnight and neutralized with 1 N HCl aqueous solution. The solid was collected and divided into three microwave vial. Each was added AcOH (8 mL) and H2O (1 mL), and heated at 180° C. for 15 min under microwave irradiation. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a yellow solid (500 mg). LCMS m/z=216.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.45 (s, 3H), 3.21 (t, J=6.5 Hz, 2H), 3.68 (s, 3H), 4.40 (t, J=6.2 Hz, 2H), 6.98 (s, 1H), 7.13 (d, J=9.0 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.CC(C)([O-])C.[Na+]>>[CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][N:12]2[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2C[C@H]3NCC[C@H]32)cc1
Reactant: Brc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: c1ccc(CN2C[C@@H]3[C@H]2CCN3c2cccnc2)cc1
Yield: 98 %

Procedure:
The product from Example 18E (260 mg, 1.0 mmol) and 3-bromopyridine were processed as described in Example 1E, except that a larger amount of sodium tert-butoxide (384 mg, 4.0 mmol) was used to neutralize the salt. The crude product was purified by chromatography (SiO2, CH2Cl2:MeOH, 95:5, Rf 0.3) to provide the title compound (0.26 g, 98% yield). 1H NMR (CD3OD, 300 MHz) δ2.40 (m, 2H), 3.20 (m, 2H), 3.50-3.80 (m, 4H), 4.10 (m, 1H), 4.50 (m, 1H), 7.00-7.60 (m, 9H); MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1.[H-].[Na+].[CH3:11]I>O1CCCC1>[Br:1][CH2:2][C:3]1([CH2:7][O:8][CH3:11])[CH2:6][O:5][CH2:4]1
Reactant: CI
Reactant: OCC1(CBr)COC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(CBr)COC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
To a stirring solution of (3-Bromomethyl-oxetan-3-yl)-methanol (200 mg, 1.104 mmol) in tetrahydrofuran (15 mL) at 0° C., was added sodium hydride (63 mg, 2.65 mmol) and stirred for 15 min. To this methyl iodide (629 mg, 4.419 mmol) was added to the above reaction mixture and the resultant reaction mixture was warmed to RT and stirred for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 3-(bromomethyl)-3-(methoxymethyl)oxetane as a liquid (120 mg, 55%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
To the product from Example 137B (70 mg, 0.1505 mmol) was treated with p-toluidine (16 mg, 0.1505 mmol), triethylamine (0.025 mL, 0.1806 mmol) and dichloromethane (4 mL) following the procedure from Example 137C to provide the title compound as an off white solid after chromatography (64 mg, 80%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 2.27 (s, 3 H) 3.17-3.30 (m, 1 H) 3.78 (s, 3 H) 7.00 (d, J=8.82 Hz, 2 H) 7.14 (d, J=8.09 Hz, 2 H) 7.40 (d, J=8.82 Hz, 2 H) 7.62 (d, J=8.46 Hz, 1 H) 7.80 (d, J=8.09 Hz, 1 H) 7.99 (s, 1 H) 8.59 (s, 1 H) 8.86 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.20 (s, 1 H); MS (APCI) m/z 536 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([OH:17])=O)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:40][C:41]1[CH:46]=[CH:45][C:44]([C@H:47]([NH2:49])[CH3:48])=[CH:43][CH:42]=1>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:17])[NH:49][C@@H:47]([C:44]2[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=2)[CH3:48])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)n2c1COCC2
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)n2c1COCC2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid 8-ethyl ester (Comp. No. 5a) (6.09 g, 25.5 mmol) in dimethylformamide (60 ml) was added 1-hydroxybenzotriazole (3.785 g, 0.028 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.37 g, 28 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(4-fluoro-phenyl)ethylamine (3.9 g, 28 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water to give 9.0 g (98%) of 6-[(R)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1[N:13]=[C:14]([CH2:35][CH2:36][CH3:37])[N:15]2[C:20]=1[C:19](N1C=NC=N1)=[N:18][C:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])=[N:16]2>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:19]2[C:20]3=[C:12]([CH3:11])[N:13]=[C:14]([CH2:35][CH2:36][CH3:37])[N:15]3[N:16]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH2:33][CH3:34])[N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc(C)c2c(-n3cncn3)nc(-c3ccccc3OCC)nn12
Reactant: NCCc1cccc(Cl)c1
Solvent: CCN(CC)CC
Product: CCCc1nc(C)c2c(NCCc3cccc(Cl)c3)nc(-c3ccccc3OCC)nn12

Procedure:
In a parallel synthetic run, 18.7 mg (0.12 mmol) of 2-(3-chlorophenyl)ethylamine are introduced into a reaction vessel and treated with 1,2-dichloroethane solutions of Example 39A and triethylamine. The amount added is 29.1 mg (0.08 mmol; solution: 0.08 mol/l) of Example 39A and 8.10 mg (0.08 mmol; solution: 0.08 mol/l) of triethylamine.