Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C@H:14]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:46](Cl)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>N1C=CC=CC=1>[C:46]([O:11][CH2:10][C@H:8]1[O:9][C@H:1]([O:12][CH2:13][C@H:14]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@H:6]1[OH:7])([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCOC[C@H](CO[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)OCCCCCCCCCCCCCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOC[C@H](CO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](O)[C@H](O)[C@H]1O)OCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 7 h
Yield: 85.2 %

Procedure:
3-O-(α-D-Galactopyranosyl)-1,2-di-O-tetradecyl-Sn-glycerol (3) (647 mg) was dissolved in pyridine (5 ml). Trityl chloride (558 mg) was added to the solution. The mixture was stirred at 60° C. for 7 hours and concentrated in vacuo. The residue was subjected to column chromatography (SiO2, C-300, 50 g) and eluted with 5% methanol-containing chloroform to obtain 3-O-(6-O-trityl-α-D-galactopyranosyl)-1,2-di-O-tetradecyl-Sn-glycerol (4) (758 mg, 85.2%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:25])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
A solution of 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.44 mmol), K2CO3 (124 mg, 1.89 mmol) in DMF (5 mL) was stirred at RT and CH3I (182 mg, 1.32 mmol) was added dropwise. The reaction was stirred at RT for 3 h. The reaction was concentrated, washed with H2O and filtered to give 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, yield: 73%). 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.78 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 5.88 (s, 1H), 3.34 (s, 3H), 3.10 (s, 3H), 3.05 (d, J=5.2 Hz, 3H). MS (M+H)+: 462/464.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[C:9](/[NH:12][C:13](=[O:21])[O:14]C2C=CC=CC=2)=[N:10]/O)=[CH:4][C:3]=1[Cl:22]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:12][C:13](=[O:21])[O:14][N:10]=2)=[CH:4][C:3]=1[Cl:22]
Reactant: O=C(N/C(Cc1ccc(Br)c(Cl)c1)=N\O)Oc1ccccc1
Solvent: Cc1ccccc1
Product: O=c1[nH]c(Cc2ccc(Br)c(Cl)c2)no1
Yield: 82.2 %

Procedure:
(Z)-Phenyl 2-(4-bromo-3-chlorophenyl)-1-(hydroxyimino)ethylcarbamate (Intermediate 23-2; 2 g, 5.21 mmol) was dissolved in anhydrous toluene (65.2 mL). The resulting solution was stirred at reflux for 16 hours. The cooled reaction mixture was evaporated to dryness and redissolved in DCM (50 mL) and extracted with saturated NaHCO3 (50 mL). The aqueous layer was acidified with 2M HCl and extracted with EtOAc (3×50 mL). The organic layers were combined and dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography {CombiFlash Companion—Presearch Ltd}, column size=120 g, flow rate=85 mL/min, elution gradient 0 to 10% MeOH in DCM}. Pure fractions were evaporated to dryness to afford 3-(4-bromo-3-chlorobenzyl)-1,2,4-oxadiazol-5(4H)-one (1.240 g, 82%) as a colourless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:36]=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:36]=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: C#CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: C#CCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-Amino-N-prop-2-ynyl-benzamide (4.20 g, 24.1 mmol) was dissolved in N,N-dimethylformamide (100 mL, 1.290 mol) and potassium carbonate (5.00 g, 36.2 mmol) was added. 2,4,5-Trichloro-pyrimidine (3.32 mL, 28.9 mmol) was added and the reaction was stirred for 48 hours. The reaction was concentrated under reduced pressure and the residue was taken up in DCM (300 mL) and washed with water (300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-prop-2-ynyl-benzamide as a pale yellow solid (298 mg, 4%). m.p.=188-191° C.; LCMS (m/e) 321 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.53 (s, 1H), 8.76 (d, 1H, J=8.5 Hz), 8.25 (s, 1H), 7.66-7.53 (m, 2H), 7.23-7.14 (m, 1H), 6.39 (bs, 1H), 4.34-4.25 (m, 2H), 2.34 (t, 1H, J=2.5 Hz). 1387c) 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-prop-2-ynyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a white solid (59 mg, 34%). m.p.=165-167° C.; LCMS (m/e) 505 M+H); 1H-NMR (CDCl3, 400 MHz) δ 10.91 (s, 1H), 8.69 (d, 1H, J=8.9 Hz), 8.11 (s, 1H), 7.55 (d, 1H, J=7.5 Hz), 7.50-7.43 (m, 1H), 7.35 (s, 1H), 7.28-7.22 (m, 1H), 7.16-7.08 (m, 1H), 7.04 (d, 1H, J=8.8 Hz), 6.87 (s, 1H), 6.32 (bs, 1H), 4.32-4.26 (m, 2H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.97-2.87 (m, 4H), 2.80-2.69 (m, 6H), 2.35-2.31 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([C:15]#[N:16])=[CH:14][C:5]2=1.C[Li].[O:19]1[CH:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH:21]([OH:19])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]1[CH:11]=[N:12][C:13]([C:15]#[N:16])=[CH:14][C:5]2=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: N#Cc1cc2c(cn1)[nH]c1ccc(Br)cc12
Agent: [Li]C
Product: N#Cc1cc2c3cc(Br)ccc3n(CC(O)COc3ccccc3)c2cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
6-bromo-9H-pyrido[3,4-b]indole-3-carbonitrile (21.3 mg, 0.785 mmol) was added to a flask and purged with nitrogen. THF was added and the solution was cooled to −78° C. Methyl lithium (1.6 M in Et2O) (1.1 eq) was added and was stirred for 30 minutes. 1,2-epoxy-3-phenoxypropane (0.011 mL, 0.824 mmol) was added with gradual warming to 45° C. Upon completion the reaction was quenched with 1 N HCl and extracted 3× with EtOAc. The organic layer was washed with H2O, brine, and dried over Na2SO4. The crude mixture was purified on SiO2 (0 to 50% EtOAc/hexanes to afford the desired product in 90% yield.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:30][CH2:29]1
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(CCc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[2-(N-methylpiperazino)-ethyl]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[C:6]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: Cc1cccc2c1CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2c(C)cccc2C1=O
Yield: 67 %

Procedure:
A solution of 13.0 g of 4-methyl-1-indanone, 19.2 ml of 3-buten-2-ol and 170 mg of p-toluenesulfonic acid in 170 ml of 2,2-dimethoxy-propane was boiled under reflux for 46 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 12.0 g (67%) of (RS)-2-(2-buten-1-yl)-4-methyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>C(Cl)Cl>[O:7]([C:1]1[CH:2]=[CH:3][C:4]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of diphenyl ether 1a (2.00 g, 11.8 mmol) in dry CH2Cl2 (30 mL) under an argon atmosphere at 0° C., was added chlorosulphonic acid (0.80 mL, 11.8 mmol). The reaction mixture was stirred for 2 h at 0° C. The solvent was evaporated at room temperature and the residue dried overnight under vacuum to give the corresponding 4-phenoxybenzenesulphonic acid (2a) as pink oil. Compound 2a was used for the next reaction without further work-up.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1c2ccc(OCCCBr)cc2C1CN1CCCCC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1c2ccc(OCCCN=[N+]=[N-])cc2C1CN1CCCCC1

Procedure:
Sodium azide (1.49 g) is added to a stirred solution of 5-(3-bromopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene (7.3 g) dissolved in a mixture of ethanol/water (7.3 ml/73 ml). The reaction mixture is refluxed overnight, poured into water and extracted with ether. The organic extract is washed with sat'd aqueous NaCl, dried, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24]O>>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1ccc(CO)c(Cl)c1
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(Cl)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-chloro-4-ethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.6 Hz), 2.65 (2H, q, J=7.6 Hz), 5.30 (2H, s), 5.80 (1H, d, J=2.0 Hz), 7.12-7.14 (1H, m), 7.26 (1H, s), 7.39 (1H, dd, J=1.6 Hz, 4.8 Hz), 7.43 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.0 Hz), 8.06 (1H, s), 8.71 (1H, d, J=4.4 Hz). [M+H] Calc'd for C18H15ClN4O, 339; Found, 339.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][NH:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[C:8]([CH3:57])[CH:7]=1.[CH2:58]([NH:65][CH2:66][CH2:67][C:68]([NH2:70])=[O:69])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.[I-].[Na+].Cl>C(#N)C.C(O)C>[CH2:58]([N:65]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][NH:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[C:8]([CH3:57])[CH:7]=1)[CH2:66][CH2:67][C:68](=[O:69])[NH2:70])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: Cc1cc(OCCCCl)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Reactant: NC(=O)CCNCc1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: Cc1cc(OCCCN(CCC(N)=O)Cc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Temperature: 70 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
A mixture of 4-{[4-(3-chloropropoxy)-2-methylphenyl]-methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.34 g), 3-benzylaminopropionamide (0.73 g), sodium iodide (0.24 g), ethanol (6 mL) and acetonitrile (6 mL) was stirred at 70° C. for 2 days. To the reaction mixture was added sodium iodide (0.2 g), and the mixture was further stirred at 75° C. for 24 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/5−dichloromethane/methanol=15/1) to give the title compound (0.97 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:10]([Cl:9])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1ccc(COc2ccc(Br)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromophenol (1.07 g, 6.18 mmol), 3,4-dichlorobenzyl alcohol (1.42 g, 8.02 mmol), and triphenylphosphine (2.10 g, 8.01 mmol) were dissolved in tetrahydrofuran (30 mL), and a diethyl azodicarboxylate toluene solution (2.2M, 3.65 mL, 8.03 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (2.25 g, quantitative).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH2:11][C:12]#[N:13])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].CO>B.C1COCC1>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][NH2:13])[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: N#CCCN(CCC#N)CCC#N
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NCCCN(CCCN)CCCN
Yield: 59.4 %

Procedure:
Tris(2-cyanoethyl)amine (2.80 g, 15.9 mmol) was dissolved in BH3.THF and refluxed under nitrogen for 48 h. MeOH (ca. 20 cm3) was added dropwise to the solution with vigorous stirring until no more gas was evolved. The solution was evaporated to dryness under vacuum and the resultant white precipitate refluxed in 6M hydrochloric acid (250 cm3) until the solution cleared. The hydrochloric acid was removed under reduced pressure and the resultant solid was dissolved in the minimum amount of water. The solution was divided up into two portions. Each portion was applied to a basic ion exchange column (DOWEX ion exchange resin, 20-50 mesh) and the amine eluted in water (ca. 250 cm3). The water was removed under reduced pressure to yield Tris(3-aminopropyl)amine (1.78 g, 59%) as a clear oil.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]([CH3:31])[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C>ClCCCl>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:4]2[CH2:3][CH2:2][N:1]([CH:21]3[CH2:20][CH2:19][C:18]([N:17]([CH3:31])[CH3:16])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22]3)[CH2:6][CH:5]=2)=[CH:8]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(N2CC=C(c3c[nH]c4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (182 mg, 1 mmole) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) were dissolved in dry 1,2-dichloroethane (10 ml). Glacial acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (4×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which could not be separated by chromatography. The diastereoisomer mixture was obtained as a colourless solid in a yield of 320 mg (80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[C:4](/[C:17](/[CH3:29])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>>[Cl:1][C:2]1[C:3]([O:30][CH3:31])=[C:4](/[C:17](/[CH3:29])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/C)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Product: COc1c(/C(C)=C\C=C\C(C)=C\C(=O)O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, ethyl 7-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-octa-2E,4E,6Z-trienoate (Compound 39, 53 mg, 0.12 mmol) was hydrolyzed with 1M NaOH. Purification by column chromatography (silica gel, 20% to 30% ethyl acetate in hexanes) followed by recrystallization from acetonitrile gave rise to the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH3:25])=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: CC1CCCN1
Product: Cc1nc2ccc(N3CCCC3C)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 21 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and 2-methylpyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 21%; MS: m/z=399. (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:33])[C:20]([O:26][CH:27]([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:21][CH:22]=3)[C:17]2=[O:34])=[C:13]([CH3:35])[CH:12]=[C:11]([CH3:36])[N:10]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:33][C:19]1[C:20]([O:26][CH:27]([CH3:32])[C:28]([F:31])([F:29])[F:30])=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:34])[N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:36])=[CH:12][C:13]=1[CH3:35])[CH2:25][CH2:24]2
Reactant: Cc1cc(C)c(CN2CCc3ccc(OC(C)C(F)(F)F)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CN2CCc3ccc(OC(C)C(F)(F)F)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-[(1,1,1-trifluoropropan-2-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-one (58b, 70 mg, 0.14 mmol) in CH2Cl2 (5 mL) was added TFA (1 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The residue was purified by column chromatography (EtOAc) to give the title compound (Example 58, 20 mg, 34%) as a white solid. 1H NMR (400 MHz, chloroform): δ 11.16 (s, 1H), 7.08-7.05 (d, 1H), 7.00-6.98 (d, 1H), 5.94 (s, 1H), 4.75 (s, 2H), 4.57-4.54 (t, 1H), 3.55 (s, 2H), 2.77 (s, 2H), 2.33-2.25 (d, 6H), 1.55 (s, 3H); MS 428.9 [M+H].
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13][NH:14][CH:15]1[CH2:17][CH2:16]1)([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13][N:14]([CH:15]1[CH2:16][CH2:17]1)[CH3:19])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ccc(Br)cc1CNC1CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(C)OC(=O)c1ccc(Br)cc1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A solution of 4-bromo-2-cyclopropylaminomethyl-benzoic acid isopropyl ester (Intermediate 119, 1.33 g, 4.26 mmol) in acetone (8 mL) was treated with potassium carbonate (2.36 g, 17.05 mmol) and methyl iodide (0.53 mL, 8.52 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered over a short bed of silica gel (230-400 mesh) and evaporated in vacuo to afford the title product (1.23 g, 70%).