Azzindani/Open_Reaction_Data huggingface dataset:
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][N: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](=[O:41])[CH3:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39](=[O:41])[CH3:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(C)=O
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N-methylacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:21])=[N:7][C:8]2[CH:9]=[C:10]3[O:20][CH2:19][CH2:18][O:17][C:11]3=[CH:12][C:13]=2[C:14]=1[CH2:15]Cl)=[O:4].C(Cl)Cl.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:21])=[N:7][C:8]2[CH:9]=[C:10]3[O:20][CH2:19][CH2:18][O:17][C:11]3=[CH:12][C:13]=2[C:14]=1[CH2:15][N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1c(Cl)nc2cc3c(cc2c1CCl)OCCO3
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(Cl)nc2cc3c(cc2c1CN1CCN(C)CC1)OCCO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 4-necked 5-L round-bottom flask is equipped with a mechanical stirrer and 250-mL addition funnel. Under nitrogen, the flask is charged with 7-chloro-9-chloromethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester, prepared as in example 13c (6, 340 g, 1.04 mol), and methylene chloride (2 L). To the stirred solution is added N-methylpiperazine (237 mL, 2.14 mol) over 10 min. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 h. The reaction mixture is poured into water (3 L) and the organic layer is separated. The aqueous layer is extracted with methylene chloride (3×2 L). The combined organic layers are washed with brine (2 L), dried over anhydrous sodium sulfate and concentrated in vacuo The resultant thick brown slurry is successively treated with methylene chloride (300 mL) and hexane (1.5 L). The mixture is swirled at 0° C. for 30 min. The precipitate is collected on a Buchner funnel, washed with hexane (1 L) and dried in vacuo. at 30° C. yielding 7-chloro-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow powder: mp 143° C. 1H NMR (CDCl3, 200 MHz) d 2.28 (s, 3H), 2.38-2.49 (m, 8H), 3.81 (s, 2H), 3.96 (s, 3H), 4.59 (s, 2H), 4.40 (s, 4H), 7.45 (s, 1H), 7.65 (s, 1H). Elemental analysis: Calculated for C19H22ClN3 O4 : C 58.24, H 5.66, N 10.72. Found: C 58.08, H 5.72, N 10.63.
Reaction SMILES: OC1CC2N([C:10]([C:12]3[CH:24]=[CH:23][C:15]4[N:16]([CH2:19][CH2:20][C:21]#[N:22])[CH:17]=[N:18][C:14]=4[CH:13]=3)=[O:11])C(CC2)C1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:22]1[C:21]([CH2:20][CH2:19][N:16]2[C:15]3[CH:23]=[CH:24][C:12]([CH:10]=[O:11])=[CH:13][C:14]=3[N:18]=[CH:17]2)=[N:27][N:26]=[N:25]1
Reactant: N#CCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)ncn2CCc1nnn[nH]1
Temperature: 100 °C

Procedure:
To a solution of 3-[5-(3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl]-propionitrile (250 mg, 0.7 mmol) in DMF (5 mL) was added sodium azide (184 mg, 2.83 mmol) and ammonium chloride (152 mg, 2.83 mmol) and heated to 100° C. for 12 h. The solvent was evaporated completely; methanol (20 mL) was added and filtered. The filtrate was concentrated and the residue purified by preparative HPLC to give 36 mg (13%) of 3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{1-[2-(1H-tetrazol-5-yl)-ethyl]-1H-benzoimidazol-5-yl}-methanone. MS-ESI m/z 368 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 1.3-2.0 (m, 8H), 3.15 (s, 1H), 3.5 (t, 2H), 3.9-4.0 (m, 2H), 4.6 (br, 1H), 4.75 (t, 2H), 7.4 (dd, 1H), 7.6-7.7 (m, 2H), 8.25 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:2]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 145.2 %

Procedure:
A 100 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.500 mL, 4.71 mmol), Piperidin-4-ol (0.619 g, 2.30 mmol) and dioxane (9.0 mL). To the resulting solution, diisopropyl ethyl amine (0.463 mL, 6.12 mmol) was added dropwise, and the reaction was allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×˜50 mL), and brine (2×˜50 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording a yellow solid (0.742 g, 3.34 mmol, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1>O.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:11](=[O:13])[CH2:10][C:9]([CH3:15])([CH3:14])[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(CC(=O)O)Sc1cccc(Cl)c1
Solvent: CCOCC
Solvent: O
Product: CC1(C)CC(=O)c2ccc(Cl)cc2S1
Temperature: 70 °C
Yield: 87.3 %

Procedure:
To 270 g of polyphosphoric acid heated to 70° C. was added, portionwise, 31.9 g of the product from Step A over 15 min with mechanical stirring under a nitrogen atmosphere. After heating at 70° C. for an additional 45 min, the reaction mixture was cooled to 0° C. and 150 ml of water was carefully added followed by 100 ml of ether. The resulting mixture was further diluted with 170 ml of water and 110 ml of ether. The layers were separated and the aqueous layer was extracted with ether (2×200 ml). The combined ether layers were washed with 100 ml of 1N NaOH and were then dried (MgSO4) and concentrated under reduced pressure to give 25.8 g of a yellow solid. The 1H NMR was consistent with a 68:32 mixture of the structure for Step B and its 5-chloro isomer, respectively.
Reaction SMILES: CO[C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[N:4]=1.[NH3:13]>O>[NH2:13][C:3]1[N:4]=[C:5]([O:11][CH3:12])[N:6]=[C:7]([O:9][CH3:10])[N:8]=1
Reactant: N
Reactant: COc1nc(OC)nc(OC)n1
Solvent: O
Product: COc1nc(N)nc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10.1 g (0.059 mole) of 2,4,6-trimethoxy-1,3,5-triazine and water (100 mL) was stirred at 25° C. while 110 mL of 28% aqueous ammonia was added. The mixture was held at 48-51° C. for two hours before it was cooled to 25° C. and the insoluble white crystals were removed. The product was washed with water and dried to give 7.84 g (86%), mp 218-221° C. 1H NMR (DMSO-d): 3.81 (s, 6H); 7.38 (s, 2H). 13C NMR (DMSO-d6): 53.9, 169.0, 171.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19]>CC(C)=O>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21]([NH:20][C:18]([O:17][CH3:16])=[O:19])=[S:22])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH2:10][CH2:11][CH3:12]
Reactant: COC(=O)N=C=S
Reactant: CCCCSc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: CCCCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
2.5 G. of 1-amino-4-n-butylthio-2-nitrobenzene (alternatively prepared according to Example II) is dissolved in 25 ml. acetone and treated at room temperature with 3 g. methoxy carbonyl isothiocyanate. The mixture is left overnight, stripped under vacuum and the residue triturated with methanol and recrystallized from methanol to yield pure 4-n-butylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=3)[CH2:23][N:24]([CH3:33])[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[N:16]=2)=[CH:11][C:10]=1[CH2:37][O:38][CH3:39])[CH3:2].[ClH:40].O1CCOCC1>>[ClH:40].[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=3)[CH2:23][N:24]([CH3:33])[CH2:25][C:26]([OH:28])=[O:27])[N:16]=2)=[CH:11][C:10]=1[CH2:37][O:38][CH3:39])[CH3:2]
Reactant: CCc1ccccc1-c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1COC
Agent: Cl
Solvent: C1COCCO1
Product: CCc1ccccc1-c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)O)c3)no2)cc1COC
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To, tert-butyl N-(3-{5-[2′-ethyl-2-(methoxymethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)-N-methylglycinate obtained in step 1 was added HCl 4M in dioxane (5.92 mL; 4 M; 23.69 mmol). The mixture was stirred at RT for 16 h. Solvents were concentrated to dryness to afford the title compound as a white powder (189 mg; 78%). 1H NMR (DMSO-d6, 300 MHz) δ 8.34 (t, J=1.7 Hz, 2H), 8.23 (d, J=7.6 Hz, 1H), 8.17 (dd, J=7.9, 1.8 Hz, 1H), 7.8 (d, J=7.6 Hz, 1H), 7.72 (t, J=7.5 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.42-7.40 (m, 2H), 7.34-7.26 (m, 1H), 7.12 (d, J=7.3 Hz, 1H), 4.50 (s, 2H), 4.26-4.12 (m, 4H), 3.27 (s, 3H), 2.82 (s, 3H), 2.46-2.23 (m, 2H), 1 (t, J=7.5 Hz, 3H). LC/MS (Method B): 470.3 (M−H)−, 472.3 (M+H)+. HPLC (Method A) Rt 4.28 min (Purity: 98.9%). CHN analysis: [C28H29N3O4.HCl.0.04 Dioxane.0.2H20] Calculated: C, 65.66%; H, 6.01%; N, 8.16%; Cl, 6.88%. Found: C, 65.50%; H, 5.86%; N, 8.37%; Cl, 6.98%.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23](=[O:34])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[CH2:18][CH2:17][CH2:16]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:40]([O:39][C:37]([CH2:36][N:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[CH2:18][CH2:17][CH2:16]2)=[O:38])[CH3:41]
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NCc4cccc5ccccc45)ccc32)cc1
Reactant: CCOC(=O)CI
Product: CCOC(=O)CN(Cc1cccc2ccccc12)c1ccc2c(c1)CCCN2C(=O)CCc1ccc(C#N)cc1

Procedure:
Prepared from 6-[(naphthalin-1-ylmethyl)-amino]-1-[3-(4-cyano-phenyl)-propionyl]-1,2,3,4-tetrahydro-quinoline (see Example 14(1)) and ethyl iodoacetate
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH:18]([CH3:20])[CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-]>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[C:9]=2[C:12]=1[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1oc2ccc(Cl)c(OC(C)C)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)oc2ccc(Cl)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To 110 mg of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 mL of THF and 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O) was added. The mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and resulting suspension was filtered. The solid product was dried under vacuum to give 94 mg (94% yield) of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH:7]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(CC(C)C)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(CC(C)C)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step A of Example 1 from 3-{3-[(4-isobutyl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, 2H), 7.57 (m, 1H), 7.52 (m, 2H), 7.11 (m, 1H), 7.03-6.86 (m, 6H), 6.79 (s, 1H), 4.29 (s, 2H), 4.28 (s, 2H), 3.67 (s, 3H), 2.80 (t, 2H), 2.50 (t, 2H), 2.40 (d, 2H), 1.80 (m, 1H), 0.86 (m, 6H); MS 480 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1[C:12]1[C:13]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:14][N:15]([CH3:17])[CH:16]=1)(=O)C.[OH-].[Na+].C(Cl)Cl>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:13]2[C:12]([C:7]3[C:8]([CH3:11])=[N:9][O:10][C:6]=3[CH2:5][OH:4])=[CH:16][N:15]([CH3:17])[N:14]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: CC(=O)OCc1onc(C)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1noc(CO)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of (4-(3-(4-chlorobenzoyl)-1-methyl-1H-pyrazol-4-yl)-3-methylisoxazol-5-yl)methyl acetate (0.3 g, 0.8 mmol) in THF (10 mL), was added NaOH solution (5 mL, 1 N in water). The mixture was stirred for 2 hours at 55° C. After cooling to room temperature, DCM (50 mL) was added and the layers separated. The separated organic layer was dried over anhydrous sodium sulfate and concentrated to afford the titled product as a yellow oil (0.2 g, 75% yield). LC/MS m/z 331 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.13 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 3H), 4.62 (s, 2H), 4.07 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][N:14]([CH3:28])[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][CH:18]2[CH2:17][CH2:16][C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([N:14]([CH3:28])[CH3:13])[CH2:20][CH2:19]2)=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(NCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.12 g tryptamine and 1.52 g 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry tetrahydrofuran (12 ml) and 1,2-dichloroethane (40 ml) under argon. Glacial acetic acid (801 μl) and 1.92 g sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for four days at RT. For working up, the reaction mixture was concentrated and the residue was taken up in water (20 ml), two molar hydrochloric acid (5 ml) and ether (35 ml). The aqueous phase was separated off, washed with ether (2×15 ml), adjusted to pH 11 with sodium hydroxide solution and extracted with ethyl acetate (3×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The beige-brown residue obtained (2.0 g) was chromatographed over silica gel with methanol which contained 0.75 vol. % triethylamine. 553 mg of the nonpolar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained (m.p. 175-178° C.), from which the corresponding dihydrochloride was obtained with chlorotrimethylsilane in 2-butanone/acetone (20 ml/50 ml) (600 mg; m.p. 216-218° C.).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([OH:15])[CH3:14])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:3]([O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([O:15][C:18]1[C:19]2[C:26]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=3)=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1)[CH3:14])([CH3:4])([CH3:6])[CH3:5]
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Reactant: C[C@@H](O)CCCCC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@H](C)CCCCC(=O)OC(C)(C)C)c23)cc1

Procedure:
Add 87 mg (2.16 mmol) sodium hydride (60% dispersion in mineral oil) to a solution of 350 mg (1.73 mmol) (6R)-6-hydroxyheptanoic acid tert.-butyl ester in 5 ml THF, with ice cooling. After stirring for ten minutes with ice cooling, add a solution of 712 mg (90% purity, 1.82 mmol) 4-chloro-5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidine in 5 ml THF and 32 mg (0.09 mmol) tetra-n-butylammonium iodide. Stir the reaction mixture for 48 hours at room temperature. After adding water and ethyl acetate, wash the separated organic phase with 1 N hydrochloric acid and concentrate by vacuum evaporation. Take up the residue in acetonitrile/DMSO and purify by preparative RP-HPLC (gradient: water/acetonitrile). 459 mg (51% of theor.) of the desired product is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CN(c2ccc(C#N)cc2)n2cnnc2)cc1

Procedure:
Starting Compounds: 4-[N-(4-cyanophenyl)amino]-4H-1,2,4-triazole and methyl 4-bromomethylbenzoate
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:13][C:14]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].S(=O)(=O)(O)O.B(O)(O)O>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:15]=1[C:16]([O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1)=[O:17]
Reactant: CCCCCc1ccc(O)cc1
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(OC(=O)c2ccc(O)cc2Cl)cc1

Procedure:
To a suspension of p-pentylphenol (0.15 mole) and 2-chloro-4-hydroxybenzoic acid (0.10 mole) in toluene (500 ml.) is added concentrated sulfuric acid (0.5 g.) and boric acid (0.31 g.) (5 mole percent). The reaction mixture is refluxed for 29 hours under a Dean-Stark trap. The solvent is then removed under reduced pressure and the product is washed with ligroin. The resulting 4-pentylphenyl 2-chloro-4-hydroxybenzoate is recrystallized from an ethanol/water mixture to give 25.6 g., 81% of pure product, m.p. 149°-151°C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:24][CH2:25][CH2:26][C:27](OCC)=[O:28])[C:6]=2[C:5]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:4][CH:3]=1.[BH4-].[Li+].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:6]=2[C:5]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cnc(N3CCCC3)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N4CCCC4)cc3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
To a solution of ethyl 4-{4-chloro-7-(1-ethylpropyl)-2-[(4-methyl-6-pyrrolidin-1-ylpyridin-3-yl)amino]-1H-benzimidazol-1-yl}butanoate (650 mg, 1.27 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (84 mg, 3.82 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 24 hr. Aqueous ammonium chloride was added and the mixture was stirred for 30 minutes followed by addition of aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a light brown solid, which was recrystallized from ethyl acetate/isopropyl ether to give the title compound (375 mg, 0.798 mmol, 63%) as a colorless solid.
Reaction SMILES: [CH3:1][P:2]([O:6][CH3:7])(=[O:5])OC.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].COC>CO>[CH3:7][O:6][P:2]([CH3:1])([CH2:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])=[O:5]
Reactant: COP(C)(=O)OC
Reactant: C=CC(=O)OC
Agent: COC
Solvent: CO
Product: COC(=O)CCP(C)(=O)OC
Yield: 97.7 %

Procedure:
80 g of methanol are mixed at room temperature under nitrogen with 216 g of dimethyl methanephosphonate and the mixture is treated dropwise at room temperature with 172 g of methyl acrylate, the temperature rising to 70° C. At the end of the dropwise addition the mixture is further stirred for 1 hour, at the end of which period about 90 g of dimethyl ether have separated in a fitted cooling trap. Excess methanol used as solvent is then removed by vacuum distillation. The crude product is obtained in a yield of 365 g with a 96.4% purity, which represents a theoretical yield of 97.7%. The boiling point of a distilled sample is 96° C. at 0.027 mbar. The 1H-NMR spectrum and the CHP analysis of the product correspond to those of a comparison sample, synthesized by an independent route.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Cl-:24].CN(C=O)C>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([Cl:24])=[O:23])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: [Cl-]
Reactant: O=C(O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2cc(-c3cccc4cnccc34)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(isoquinolin-5-yl)-1-naphthoic acid (0.123 g, 0.4 mmol) was suspended in CH2Cl2 (15 mL) and oxallyl chloride was (0.036 mL, 0.4 mmol) was added followed by a drop of DMF. The resulting mixture was stirred at room temperature overnight and the solvent was evaporated to give a solid. The solid was dried under vacuum.