Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCC1.[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH2:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:22][CH2:21]2)=O)=[C:10]([N:34]2[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH:9]=1.O.[ClH:40]>C(O)C>[OH2:1].[ClH:40].[ClH:40].[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH2:16][CH2:17][CH2:18][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:22][CH2:21]2)=[C:10]([N:34]2[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH:9]=1.[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH2:16][CH2:17][CH2:18][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:22][CH2:21]2)=[C:10]([N:34]2[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH:9]=1.[ClH:40].[ClH:40]
Reactant: C1CCOC1
Reactant: COc1cc(CCC(=O)N2CCN(c3ccccc3OC)CC2)c(-n2cccc2)cc1OC
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(CCCN2CCN(c3ccccc3OC)CC2)c(-n2cccc2)cc1OC
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To 100 ml of tetrahydrofuran were added 18 ml of 1.0M borane-tetrahydrofuran complex and 1.14 g of 1-(3-(4,5-dimethoxy-2-(1-pyrrolyl)phenyl)-1-oxopropyl)-4-(2-methoxyphenyl)piperazine at room temperature, and the mixture was heated under reflux for 27 hours. Since it was found that the reaction had not completed, 10 ml of the borane-tetrahydrofuran complex was further added, and the refluxing was continued for additional 9 hours. After cooling to room temperature, 10 ml of water was added to the reaction mixture, and the solvent was removed under reduced pressure. To the residue was added 35 ml of 5% hydrochloric acid, followed by heating at 50° to 60° C. for 2 hours. The reaction mixture was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform) to yield 780 mg of a pale yellow oily substance, which was dissolved in 15 ml of ethanol, 1.0 ml of concentrated hydrochloric acid was added thereto, and the solvent was removed under reduced pressure. Recrystallization of the residue from ethanol-ethyl ether yielded 500 mg of the title compound as a colorless prism crystal.
Reaction SMILES: [CH2:1]([C:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([C:10]#[N:11])[C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[H][H]>C(OCC)C>[CH2:12]([C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH2:8][NH2:9])[CH2:10][NH2:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(C#N)(C#N)CCCCCC
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCC(CN)(CN)CCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
2,2-Dihexylpropanedinitrile (22.0 g, 94 mmol) dissolved in dry diethyl ether (100 ml) was added slowly to a suspension of lithium aluminium hydride (8.7 g, 0.23 mol) in dry diethyl ether (250 ml) under nitrogen. Upon complete addition, the mixture was heated under reflux using a water bath for 1 h and then stirred at room temperature for 24 h. Water was carefully added to the reaction mixture with cooling of the flask in an ice bath, until no more hydrogen was evolved. The reaction mixture separated into two layers and the ether layer was decanted from the aqueous layer, washed with water, and dried with anhydrous magnesium sulphate. The ether was evaporated to yield a viscous oil that was distilled under reduced pressure to yield 2,2-dihexylpropane-1,3-diamine as a colorless liquid (11.2 g, 49%) b.p. 138°-142° C./0.7 mm.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]([NH:28][NH2:29])=[O:27])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>C1COCC1.CCOC(C)=O>[CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]2[O:27][C:31](=[O:32])[NH:29][N:28]=2)=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NN)s1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(-c2n[nH]c(=O)o2)s1
Yield: 63.2 %

Procedure:
A mixture of 5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid hydrazide (432 mg, 1 mmol), 1,1′-carbonyldiimidazole (405 mg, 2.5 mmol) and triethylame (0.28 ml, 2 mmol) in THF (10 ml) is stirred at reflux overnight. It is diluted with EtOAc, washed with 1N HCl solution. The organic phase is concentrated and chromatographed (Hex to 20% EtOAc/Hex to give the title compound (290 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)[C:5]([F:26])=[CH:4][N:3]=1>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([F:26])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc(Cl)ncc3F)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)CNCC2

Procedure:
A solution of 2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamine in 40% trifluoroacetic acid/dichloromethane was stirred at rt for 30 min. Removal of the solvent left an oily residue which was suspended in water, made basic with NaHCO3, and extracted with ethyl acetate. Purification by column chromatography over silica gel provided 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.04 (d, 1H, J=3.0 Hz), 7.37 (dd, 1H, J=2.4 and 8.4 Hz), 7.27 (d, 1H, J=1.5 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.92 (s, 1H), 4.04 (s, 2H), 3.15 (t, 2H, J=6.0 Hz), 2.79 (t, 2H, J=6.0 Hz); 19F NMR (282 MHz, CDCl3): −44648; LCMS: purity: 97%; MS (m/e): 279(MH+).
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:21][NH2:22]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:21][NH2:22])[C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1cccc2c1CC(=O)c1cc(F)ccc1S2
Solvent: CCO
Solvent: O
Product: N#Cc1cccc2c1CC(=NN)c1cc(F)ccc1S2
Yield: 95 %

Procedure:
The mixture of 0.3 g of 9-cyano-2-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one, 0.3 g of 100% hydrazine hydrate and 10 ml of ethanol was heated under reflux on waterbath for 5 hours. The reaction mixture was concentrated to 5 ml to separate crystals on cooling, which was collected by filtration. Recrystallization from ethanol afforded 0.3 g of 9-cyano-2-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one hydrazone as pale yellow needles having a melting point of 220°-222° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]1[CH:14]=[C:15]([C:22](Cl)=[O:23])[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12.Cl.O>N1C=CC=CC=1>[F:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][C:22]([C:15]1[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=[N:13][CH:14]=1)=[O:23]
Reactant: O=C(Cl)c1cnc2ccccn12
Reactant: COC(=O)c1ccc(F)c(N)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 25 °C

Procedure:
A solution of methyl 3-amino-4-fluorobenzoate (5 g, 29.6 mmol) in pyridine (200 ml) was treated with imidazo[1,2-a]pyridine-3-carbonyl chloride.HCl (step 1) (6.43 g, 29.6 mmol) and the mixture was stirred at RT for 2 days. The mixture was poured into water (30 ml) and a small exotherm was observed. After cooling to RT, the resulting precipitate was filtered and dried in a vacuum oven to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.Br[CH2:12][C:13](=O)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]2[CH:12]=[C:13]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[N:10]=[C:5]2[CH:4]=1
Reactant: COc1cc(N)nc(C)n1
Reactant: O=C(CBr)C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2nc(C(=O)c3ccccc3)cn2c(C)n1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A stirred solution of 2.1 g of 6-methoxy-2-methyl-4-pyrimidinamine in dry tetrahydrofuran was treated with a solution of 5.4 g of 3-bromo-1-phenyl-1,2-propanedione in 5 ml of dry ether. After stirring overnight, the mixture was chilled and the precipitated salt filtered off. A suspension of the salt in dry ethanol was refluxed for 1.5 hours, chilled, and filtered. The solid was shaken with a mixture of chloroform and aqueous sodium bicarbonate and the organic layer was evaporated to dryness under reduced pressure. The residue was chromatographed in ethyl acetate on silica to obtain 2.7 g of (7-methoxy-5-methyl-imidazo[1,2-c]pyrimidin-2-yl)-phenylmethanone as a yellow crystalline solid melting at 165°-7° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:10]([CH3:11])[O:9][C@@H:8]([CH3:12])[CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].I[CH2:24][C:25]#[C:26][C:27]([CH3:30])([OH:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]([C@H:5]1[C@H:10]([CH3:11])[O:9][C@@H:8]([CH3:12])[CH2:7][N:6]1[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:24][C:25]#[C:26][C:27]([OH:29])([CH3:30])[CH3:28])=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[O:4]
Reactant: CC(C)(O)C#CCI
Reactant: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(OCC#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2S,3R,6S)-4-(4-Hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester, (200 mg, 0.607 mmol) (prepared according to the methods described in U.S. patent application Ser. No. 60/096256, filed Aug. 12, 1998) was dissolved in dimethyl formamide (6 mL). 5-Iodo-2-methyl-pent-3-yn-2-ol (272 mg, 1.214 mmol) and cesium carbonate (593 mg, 1.821 mmol) were added and the reaction stirred at room temperature for 4 hours. The reaction was diluted with diethyl ether (100 mL) and washed with water (5 times 10 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound. The crude material was used directly in the preparation of Example 1 without further purification. 1HNMR (400 MHz, CDCl3): δ=7.70 (d, J=8.9 Hz, 2H), 7.0 (d, J=8.9 Hz, 2H), 4.74 (bs, 2H), 4.50 (q, J=6.6 Hz, 1H), 4.26 (s, 1H), 3.92 (m, 1H), 3.54 (s, 3H), 3.50 (m, 1H), 2.93 (dd, J=12.3 and 11.0 Hz, 1H), 1.48(s, 6H), 1.44 (d, J=5.4 Hz, 3H), 1.01(d, J=6.0, 3H). MS: Calculated for C20H27NO7S (M−OH): 408.15. Found: 408.1.
Reaction SMILES: CCCCC.C([Li])(C)(C)C.O1CCCC1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[N:26]=[C:25]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=3)[N:24]=2)=[CH:19][CH:18]=1.Br[C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][N:51]=1>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>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:26]=[C:25]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:47])([CH3:48])[CH3:46])=[CH:41][CH:40]=3)[N:24]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([C:50]4[CH:55]=[CH:54][C:53]([C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)=[CH:52][N:51]=4)=[CH:22][CH:21]=3)[N:28]=2)=[CH:34][CH:33]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccccc5)cn4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Under a stream of argon, 3.5 ml of a pentane solution containing 5.2 mmol of tert-butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C., and 10 ml of tetrahydrofuran in which 0.61 g of 2-bromo-5-phenylpyridine had been dissolved was further added dropwise to this solution. After stirring at −78° C. for 30 minutes, 1.64 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 35 ml portion of tetrahydrofuran prepared by dissolving 1.00 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine synthesized by the method of Reference Example 1 and 0.12 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 10 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:dichloromethane=3:2 to 4:3) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4-(5-phenylpyridin-2-yl)phenyl]-1,3,5-triazine (1.05 g, yield 91%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][N:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccncn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccncn3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyrimidine-4-carboxamide
Reaction SMILES: FC(F)(F)C1C=C(C(F)(F)F)C(C(N)=O)=CC=1.[NH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH:24][C:25](=[O:40])[C:26]1[C:31]([S:32][CH3:33])=[CH:30][C:29]([C:34]([F:37])([F:36])[F:35])=[CH:28][C:27]=1[O:38][CH3:39].[I-].C([N+]1(C)[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)C>>[CH3:39][O:38][C:27]1[CH:28]=[C:29]([C:34]([F:36])([F:37])[F:35])[CH:30]=[C:31]([S:32][CH3:33])[C:26]=1[C:25]([NH:24][CH:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[N:18]1[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)=[O:40]
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Agent: NC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: [I-]
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCC(=O)CC1

Procedure:
The title compound, yellow gum, MS: m/e=431.3 [(M+H)+], was prepared in accordance with the general method of intermediate J from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[CH:15][C:14]=1[N+:32]([O-:34])=[O:33]>CS(C)=O>[N+:32]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH:20]=2)[CH:17]=[CH:18][C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([O-:34])=[O:33]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(Nc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Dimethyl malonate (9.6 mL) was added dropwise to a stirred suspension of 3.2 g of 60% sodium hydride in mineral oil in 40 mL anhydrous dimethylsulfoxide under nitrogen. The mixture was stirred for 10 minutes and 2-fluoro-5-(3-trifluoroacetamidophenyl)nitrobenzene in 20 mL dimethylsulfoxide was added. The resulting dark red mixture was heated to 100° C. for 2 hours. The reaction was quenched by pouring into 100 mL of saturated ammonium chloride solution and extracted twice with 50 mL of ethyl acetate. The organic phase was washed with 50 mL each of saturated ammonium chloride solution, water, and brine, dried over anhydrous sodium sulfate and concentrated to a yellow oil. The oil was chromatographed on a column of silica gel (ethyl acetate:hexane (1:4)) to give 4.4 g (50% yield) of dimethyl 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl]malonate as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:16](=[O:17])[O:18][CH2:19][CH3:20])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cncc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
5-bromopyridin-3-amine (20 g, 116 mmol) was dissolved in DCM (500 mL) and pyridine (28.0 mL, 347 mmol) was added, followed by ethyl chloroformate (11.44 mL, 119 mmol) dropwise. The reaction mixture was stirred for 1.5 h at room temperature. The reaction mixture was diluted with DCM. The two phases were separated and the organic phase was washed with 10% CuSO4 solution (2×) sat. NaHCO3 solution (1×) Brine (1×) dried (Na2SO4) and evaporated. The residue was triturated with diethyl ether filtered and dried obtaining ethyl (5-bromopyridin-3-yl)carbamate (21.58 g, 76%) as a white solid. LCMS (m/z): 247.0 (MH+), 0.58 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.62-8.15 (m, 3H) 7.00 (br. s., 1H) 4.27 (q, J=7.0 Hz, 2H) 1.34 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:22]([N:9]1[C:10]2[C@:11]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@@H:14]([CH2:13][CH2:12]3)[C:15]=2[C:16](=[O:17])[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2F)n1Cc1ccccc1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
A solution of (4R,7S)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 38; 890 mg, 3.11 mmol), terabutylammonium iodide (860 mg, 2.33 mmol) and benzyl bromide (1.7 mL, 14.3 mmol) in dimethylformamide (15 mL) was heated in an oil-bath at 100° C. for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. Dichloromethane (100 μL) was added and the solution was washed with water (5×25 mL), aqueous sodium thiosulfate (25 mL), and brine (25 mL), dried (magnesium sulfate, filtered, and evaporated. The residue was purified using an ISCO 120 g column, eluting with 60-100% ethyl acetate/hexanes. Fractions containing the product were concentrated and then co-evaporated with ether. Petroleum ether was added and the mixture was scratched to give a solid. The solvent was evaporated and the residue was co-evaporated three times with ethanol, and then dried under high vacuum at 65° C. and then at 75° C. to give (4R,7S)-1-benzyl-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (462 mg, 39%) as a pale yellow solid. ES(+)-MS (M+H) 377.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21]Cl)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N12CCCCC1C=NCCC2.O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCCl)cc12
Agent: C1=NCCCN2CCCCC12
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCN3CCCCC3)cc12
Yield: 28.3 %

Procedure:
156 mg of 6-(3-chloro-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is stirred together with 85 mg of piperidine and 76 mg of 1.5-diazabicyclo-[5.4.0]undec-5-ene in 10 ml of absolute ethanol under nitrogen and exclusion of water for 11/2 h at 60° C. After evaporation, the residue is chromatographed on 25 g of silica gel with methylene-chloride/methanol (10/2) as the eluant. 51 mg of 6-[3-(1-piperidinyl)-1-propinyl]-beta-carboline-3-carboxylic-acid-ethylester is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:16][CH2:17][C:18](Br)=[O:19]>ClCCl.O>[Br:16][CH2:17][C:18]([NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1ccccc1C(=O)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
98.6 g of 2-aminobenzophenone were dissolved in a mixture of 650 ml of dichloromethane and 50 ml of water. A solution of 116.1 g of bromoacetyl bromide in 150 ml of dichloromethane was added dropwise to this mixture at a temperature of -10° C. The reaction mixture was then stirred at room temperature for a further 2 hours. The reaction mixture was worked up by adding water, separating the organic phase, washing again with water, drying and evaporating under reduced pressure. The crude product remaining as a residue was crystallized from ether/petroleum ether. 142 g of 2-[(2-bromoacetyl)-amino]-benzophenone having a melting point of 96-98° C. were obtained.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:11].Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:16]=1[NH:25][C:26]([NH:28][C:29]([NH2:31])=[NH:30])=[NH:27]>C(O)C>[ClH:11].[CH2:2]([CH:1]1[N:25]([C:16]2[CH:17]=[C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])[CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[C:26]([NH2:27])=[N:28][C:29]([NH2:31])=[N:30]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC=O
Reactant: COc1ccc(C(C)(C)C)cc1NC(=N)NC(=N)N
Agent: Cl
Solvent: CCO
Product: CCCCCCCCC1N=C(N)N=C(N)N1c1cc(C(C)(C)C)ccc1OC

Procedure:
100 ml of ethanol, 3.7 g (26.2 mmol) of 1-nonanal and 0.8 ml of concentrated hydrochloric acid were added to 6.0 g (20.0 mmol) of N1-(2-methoxy-5-tert-butylphenyl)-biguanide hydrochloride, and the mixture was refluxed for 20 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)). The eluate was dissolved in 80% aqueous ethanol, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol and ether to obtain 2.3 g of pale yellow crystals having a melting point of 217 to 219° C.