Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37]([C:35]5[CH:34]=[CH:33][C:32]6[O:28][CH2:29][O:30][C:31]=6[CH:36]=5)=[O:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc2c(c1)OCO2

Procedure:
The title compound, white solid (110 mg, 92%), MS (ISP) m/z=479.4 [(M+H)+], mp 213.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and benzo[d][1,3]dioxole-5-carboxylic acid.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.[C:23]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=1)#[CH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:32][O:31][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([C:23]2[CH:24]=[N:14][N:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=23)[N:30]=1
Reactant: C#Cc1nccc(OC)n1
Reactant: N#Cc1cc[n+](N)cc1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccnc(-c2cnn3ccc(C#N)cc23)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.8 %

Procedure:
1-Amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate (Preparation 2, 12.10 g, 37.88 mmol) was added in portions over 6 hours to a stirred suspension of 2-ethynyl-4-methoxypyrimidine (Preparation 1b, 2.54 g, 18.94 mmol) and potassium carbonate (3.93 g, 28.43 mmol) in anhydrous N,N′-dimethylformamide (47 mL) at 0° C. and the resulting mixture was stirred at ambient temperature for 48 hours. The solvent was evaporated and dichloromethane was added to the residue. The solid formed was filtered and the filtrate evaporated to dryness. The crude product was purified by flash chromatography (4:1 hexanes/ethyl acetate) to give the title compound (3.51 g, 74%) as a solid.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:19])[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:20]([O:22]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:21])=[CH:7][C@@H:6]1[NH:36][CH2:37]C(=O)C(F)(F)F)(=[O:3])[CH3:2].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:19])[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:20]([OH:22])=[O:21])=[CH:7][C@@H:6]1[NH:36][CH3:37])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NCC(=O)C(F)(F)F)[C@H]1NC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](NC)[C@H]1NC(C)=O
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A solution of (4S,5R,6R)-5-acetylamino-6-(dipropylcarbamoyl)-4-(2,2,2-trifluoroacetylmethylamino)-5,6-dihydro-4H-pyran-2-carboxylic acid, benzhydryl ester (0.430 g) in dichloromethane (2.5 ml) and trifluoroacetic acid (2.5 ml) was stirred at 23° C. for 2 hours. The solvent was removed in vacuo and the residue was azeotroped with toluene (2×25 ml). The residue was taken up in a water/methanol mixture (20 ml, 1:1 v/v) and stirred at 23° C. with potassium carbonate (1.0 g) for 18 hours. The solvent was removed in vacuo and the residue was purified using HPLC on a reverse phase column eluted in a gradient procedure with water and acetonitrile containing trifluoroacetic acid. The required fractions were combined and solvent was removed in vacuo to give the title compound as a white solid (0.182 g). 1H NMR (250 MHz, D6 -DMSO,) 9.00 (2H, broad s), 8.35 (1H, d, J=8 Hz), 5.92 (1H, d, J=3 Hz), 5.05 (1H, d, J=8 Hz), 4.34 (1H, m), 3.46-3.30 (2H, m), 3.25-3.10 (1H, m), 3.08-2.90 (1H, m), 2.6 (3H, s), 1.75 (3H, s), 1.60-1.48 (2H, m), 1.48-1.30 (2H, m), 0.80 (3H, t, J=8 Hz), 0.75 (3H, t, J=8 Hz). Mass spec (Low Resolution): MH+ =342. Mass spec (High Resolution): MH+ =342.202998, fits for molecular formula C16H28N3O5, error=0.3 ppm.
Reaction SMILES: [C:1]1([N:7]2[C:11](O)=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O.C(O)(=O)C.C(O)(=O)C>[C:1]1([N:7]2[CH:11]=[C:10]([Cl:17])[C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nn(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.3 %

Procedure:
A mixture of 2.28 g (10 mmol) of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole and 1.6 g (12 mmol) of N-chlorosuccinimide in 8 ml of 20% TFA/acetic acid and 32 mL of acetic acid was stirred at room temperature for 16 hours and diluted with ice/water with cooling. The white precipitate was filtered and purified by column chromatography (silica gel; 20-33% ethyl acetate/hexane) to afford 550 mg (21%) of 1-phenyl-3-trifluoromethyl-4-chloropyrazole as a solid.
Reaction SMILES: [OH-].[Na+].[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])C=CC=CC=1.[CH:38](=O)[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CS(C)=O>[C:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:25])[CH3:24]
Reactant: CCCCCC=O
Reactant: CC(=O)OCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCC/C=C\CCCCCCCCCCOC(C)=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
30 ml. of dry dimethyl sulfoxide are poured into a 200 ml. of four-necked flask equipped with a stirrer, a dropping funnel, a gas inlet tube, a thermometer and a condenser. 2.5 g. (0.13 moles) of sodium hydroxide (80% oily suspension) are introduced into the flask, and the mixture is stirred at 70° C. under argon temperature until the gas evolution ceases (0.5 hours). The reaction mixture is cooled to room temperature, a solution of 20 g. (0.036 moles) of triphenyl-(11-acetoxy-undecyl)-phosphonium bromide (Formula V, X=Br, Y=COCH3) in 20 ml. of dry dimethyl sulfoxide is added, and the resulting mixture is stirred at room temperature for 0.5 hours. There are added dropwise to the red solution 4 g. (0.04 moles) of hexanel (Formula IV, R=CH3), and the mixture is stirred at room temperature for 15 hours. The reaction mixture is poured onto 60 g. of ice, and extracted with 200 ml. of hexane. The extract is washed successively with water, 10% aqueous sulfuric acid, water, saturated aqueous sodium bicarbonate solution and again with water, dried over magnesium sulfate, filtered, and the solvent is evaporated in vacuo. 2.34 g. (22%) of (Z)-11-heptadecenyl acetate (Formula I, R=CH3) are obtained; b.p.: 122°-125° C./0.05 mmHg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[N:40][NH2:41])=[CH:35][CH:34]=1>O1CCOCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:41][N:40]=[CH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:43])[F:42])=[CH:38][CH:37]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:5]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Reactant: NN=Cc1ccc(OC(F)(F)F)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2nc(Cl)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
4,6-Dichloro-N-(3-trifluoromethyl-4-fluorophenyl)-1,3,5-triazine-2-amine (XVII) (2.0 g, 6.2 mmol) was dissolved in dioxane (40 mL). Diisopropylethyl-amine (1.6 mL, 9.32 mmol) was added followed by [4-(trifluoromethoxy)-benzylidene]hydrazine (XX) (1.3 g, 6.2 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue diluted with ethyl ether (25 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to a yellow powder. This powder was washed with acetonitrile to give {4-chloro-6-[N′-(4-trifluoromethoxy-benzylidene)hydrazino]-1,3,5-triazin-2-yl}-(4-fluoro-3-trifluoromethylphenyl)-amine (XXI) as a white solid; (2.1 g, 67% yield): m.p. 109-111° C.; 1H NMR (CDCl3): δ 8.9, (bs, 1H); 8.5 (bs, 1H); 7.95 (s, 1H); 7.75 (bs, 2H); 7.45 (bs, 1H); 7.24 (m, 4H); ESI/MS 494 (M+H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:11]([O:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21](=O)[CH2:22][C:23]#[N:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCO>[CH2:11]([O:18][CH2:19][C:20]([C:21]1[CH:22]=[C:23]([NH2:24])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[N:9]=1)([CH3:26])[CH3:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)(COCc1ccccc1)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)COCc3ccccc3)cc2N)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of p-tolylhydrazine hydrochloride (1.99 g, 12.6 mmol) and 5-(benzyloxy)-4,4-dimethyl-3-oxopentanenitrile (4.00 g, 13.8 mmol, 80% purity) in EtOH was heated at reflux for 16 hr and then cooled to RT. The mixture was neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 80 g, MeOH in DCM, 0-5%, gradient elution) to afford the title compound, (2.62 g, 60%); Rt 3.05 min (Method 1 basic); m/z 336 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:16](=[O:19])[CH2:17][CH3:18])[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C:3]([CH2:1][CH3:2])=[C:4]1[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: Clc1ccccc1CBr
Reactant: CCC(=O)c1[nH]c2cc(C(=O)OC)ccc2c1CC
Product: CCC(=O)c1c(CC)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl

Procedure:
Methyl 1-(2-chlorobenzyl)-3-ethyl-2-propionylindole-6-carboxylate (66 mg) was prepared from methyl 3-ethyl-2-propionylindole-6-carboxylate (88 mg) and 2-chlorobenzyl bromide (0.051 ml) in a similar manner to that of Example 1.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:24]=[CH:23][N:16]3[C:17](=[O:22])[CH2:18][C:19](=O)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:58][N:59]([CH3:68])[C:60]([CH:62]1[CH2:67][CH2:66][CH2:65][NH:64][CH2:63]1)=[O:61].C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:24]=[CH:23][N:16]3[C:17](=[O:22])[CH:18]=[C:19]([N:64]4[CH2:65][CH2:66][CH2:67][CH:62]([C:60]([N:59]([CH3:68])[CH3:58])=[O:61])[CH2:63]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)C1CCCNC1
Reactant: CC(C)(C)c1csc(NC(=O)C2=CC3=NC(=O)CC(=O)N3C=C2)n1
Agent: O=C([O-])O
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1CCCN(c2cc(=O)n3ccc(C(=O)Nc4nc(C(C)(C)C)cs4)cc3n2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.2 %

Procedure:
N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2,4-dioxo-3,4-dihydro-2 H-pyrido[1,2-a]-pyrimidine-8-carboxamide (301.9 mg, 0.88 mmol) was suspended in dimethylformamide (6 ml) and acetonitrile (12 ml), added dropwise with diisopropylethylamine (1.83 ml, 10.5 mmol) and diphenyl chlorophosphate (545.1 μl, 2.63 mmol) at −10° C. under an argon flow, and stirred at the same temperature for 5 minutes and at room temperature for 15 minutes. The reaction solution was cooled to −10° C. again, added dropwise with a solution of 3-[(dimethylamino)carbonyl]piperidine trifluoroacetic acid salt (1.18 g, 4.38 mmol) in dimethylformamide (5 ml), and stirred at room temperature for 1 hour and at about 80° C. for 2 hours. The reaction solution was heated to about 100° C., heated for 30 minutes with stirring, then added with diisopropylethylamine (1.83 ml, 10.5 mmol), and further heated at 100° C. for 3 hours and 30 minutes with stirring. After cooling, the solution was added with saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=50:1→20:1, v/v) and preparative TLC (chloroform:methanol=20:1, v/v) to obtain the title compound (85.9 mg, 20.3%) as yellow orange oil.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:25]=[CH:24][C:14]2[C:15]3[CH2:16][N:17]([CH3:23])[C:18](=[O:22])[C:19]=3[CH:20]=[CH:21][C:13]=2[CH:12]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH2:33]([O:36][C:37](Cl)=[O:38])[CH:34]=[CH2:35]>CN(C=O)C.O>[CH2:33]([O:36][C:37]([N:9]1[CH:10]=[C:6]([C:2]([C:11]2[CH:25]=[CH:24][C:14]3[C:15]4[CH2:16][N:17]([CH3:23])[C:18](=[O:22])[C:19]=4[CH:20]=[CH:21][C:13]=3[CH:12]=2)([OH:1])[CH:3]([CH3:5])[CH3:4])[N:7]=[CH:8]1)=[O:38])[CH:34]=[CH2:35]
Reactant: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1c[nH]cn1
Reactant: C=CCOC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)n1cnc(C(O)(c2ccc3c4c(ccc3c2)C(=O)N(C)C4)C(C)C)c1
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
7-[1-Hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (13.8 g) was suspended in DMF (400 ml) and the mixture was heated to 85° C. to give a homogeneous solution. This solution was cooled in an ice bath and triethylamine (8.6 ml) was added. Then allyloxycarbonyl chloride (5.2 ml) was slowly added and the reaction mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The extracted layers were combined, washed three times with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (carrier: silica gel, developing solvent: dichloromethane-methanol=100:1-40:1) to give the title compound (15.9 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36][OH:37])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:26]CC5C=CC=CC=5)[CH:14]=[CH:15][C:16]=4[O:18]CC4C=CC=CC=4)[C:11](=[O:34])[C:10]=1[C:9]=23.[NH2:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][NH2:44].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[NH2:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][NH:44][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36][OH:37])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([OH:26])[CH:14]=[CH:15][C:16]=4[OH:18])[C:11](=[O:34])[C:10]=1[C:9]=23
Reactant: O=C1c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2-c2nn(CCO)c3ccc(Cl)c1c23
Reactant: NCCNCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: NCCNCCNc1ccc2c3c(nn2CCO)-c2c(O)ccc(O)c2C(=O)c13
Yield: 78 %

Procedure:
A mixture of 5.1 g (10 mmol) of 5-chloro-2-(2-hydroxyethyl)-7,10-bis(phenylmethoxy)anthra[1,9-cd]-pyrazol-6(2H)-one, 10 g (100 mmol) of diethylenetriamine, 1.4 g (10 mmol) of anhydrous potassium carbonate, and 60 ml of pyridine is heated at reflux for 28 hours. The mixture is cooled, the solids are collected by filtration then washed sequentially with water and 2-propanol to give 3.1 g of the product; mp 185°-190° C.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[OH:8][C:1]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH2:13][CH2:14]1
Reactant: N#Cc1ccc(OCCCN2CCC(C(=O)c3ccccc3)CC2)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 6 h
Yield: 69.8 %

Procedure:
4-(3-(4-Benzoylpiperidin-1-yl)propoxy)benzonitrile (0.5 g, 1.4 mmol) was dissolved in dry THF (˜15 mL), and a solution of phenylmagnesium bromide (0.9 mL, 2M, 1.8 mmol) was added and the reaction stirred for 6 h. The reaction was quenched (sat. NH4Cl) and extracted into EtOAc (2×). The organic layers were dried over Na2SO4 and the volatiles removed under reduced pressure. The crude residue was purified on silica gel (EtOAc/hexanes) to give 417 mg (70% yield) of title compound Example B1: 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, d, J=8.8 Hz), 7.50 (4H, d, J=7.6), 7.30 (4H, q, J=8), 7.20 (2H, t, J=7.2 Hz), 6.94 (2H, d, J=8.8 Hz), 4.06 (2H, t, J=6 Hz), 3.07 (2H, d, J=11.2 Hz), 2.59 (2H, t, J=7.2 Hz), 2.53-2.46 (1H, m), 2.14-2.01 (4H, m), 1.66-1.55 (4H, m), LC-MS (>98%) m/z=427.0 [M+H]; HRMS=427.2386 [M+H], 100% calculated for C28H31N2O2, 427.2386.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[NH:13][C:12]=2[CH:11]=1>>[CH2:1]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27])[NH:13][C:12]=2[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Product: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(OCc3ccccc3)cc1N2
Yield: 27 %

Procedure:
2-Benzyloxy-6-dimethylsulphamoylphenothiazine (m.p. 192°-194°C.; 69.0 g.) is prepared by reacting benzyl chloride (106.0 g.) with 2-hydroxy-6-dimethylsulphamoylphenothiazine (200 g.).
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:6][C:7]([NH:23]C(=O)C)=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=1)([O-:3])=[O:2].Cl.[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[C:5]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:6][C:7]([NH2:23])=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCOc1cc([N+](=O)[O-])c(OCCCCCCCCCCCC)cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1cc([N+](=O)[O-])c(OCCCCCCCCCCCC)cc1N

Procedure:
4.6 g of the product of Stage 4 are boiled under reflux for a few hours with 1.5 ml of concentrated hydrochloric acid in ethanol until no more starting material can be detected. The mixture is then adjusted to neutral to alkaline with strong sodium hydroxide solution and precipitated with plenty of water. The deposit is filtered under suction, washed with water, stirred with acetonitrile, refiltered under suction and dried.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10]([F:13])([F:12])[CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[N:3]=1.[H-].[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:10]([F:13])([F:12])[CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][CH:27]=2)[N:3]=1
Reactant: CCCCCCCCC1CCc2cc(-c3ccc(O)cc3)nc(F)c2C1(F)F
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cc3c(c(F)n2)C(F)(F)C(CCCCCCCC)CC3)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1,8,8-trifluoro-3-(4-hydroxyphenyl)-7-octyl-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1,8,8-trifluoro-3-[4-(octyloxy)phenyl]-7-octyl-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([Sn](CCCC)(CCCC)CCCC)=[N:27][N:28]2[CH3:31])=[CH:24][CH:23]=1>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.[Cu]I>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:2]3[N:3]=[C:4]4[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]4=[N:6][CH:7]=3)=[N:27][N:28]2[CH3:31])=[CH:24][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: [Cu]I
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: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (400 mg, 1.12 mmol) and 6-chloro-1-methyl-3-tributylstannyl-1H-indazole (1.11 g, 1.7 mmol) were dissolved in DMF (10 mL). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.056 mmol) and copper(I) iodide (43 mg, 0.23 mmol) were added. The reaction mixture was stirred at 80° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-30% EtOAc) to provide 416 mg (84%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH:13]1[CH2:14][O:15]1
Reactant: BrCC1CO1
Reactant: COc1ccc(O)c(F)c1
Product: COc1ccc(OCC2CO2)c(F)c1
Yield: 48 %

Procedure:
Synthesis followed SP3a, using 3.5 mmol 2-fluoro-4-methoxyphenol and racemic epibromohydrine to give the title compound upon purification by Flash Master Personal (20 g silica gel cartridge, PE to PE/ethyl acetate 5:1) with 48% yield.