Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[S:4][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCSc1ccccc1C(=O)OC

Procedure:
A mixture of methyl thiosalicylate (3.25 g, 19.3 mmol), ethyl 4-bromobutyrate (5.7 g, 29 mmol) and potassium carbonate (5.4 g, 39 mmol) in acetone (40 mL) was heated at reflux for 1 hour, cooled and filtered to remove the solids. The solids were washed with acetone and the combined filtrates were concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of hexane:EtOAc (20:1, 10:1, 5:1 and 2:1) to provide the title compound. 1H NMR (CDCl3) δ 1.26 (t, J=7.12 Hz, 3H), 2.05 (m, 2H), 2.51 (t, J=7.29 Hz, 2H), 2.99 (t, J=7.29 Hz, 2H), 3.91 (s, 3H), 4.14 (q, J=7.12 Hz, 2H), 7.11-7.21 (m, 1H), 7.35 (m, 1H), 7.45 (m, 1H), 7.95 (dd, J=7.80, 1.70 Hz, 1H); MS (M+NH4)+ m/z 300.
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])=[CH:5][CH:4]=1.[C:24]([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[OH:26][CH2:24][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[C:10]([C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])=[O:16])[CH:11]=1
Reactant: CC(=O)[O-]
Reactant: C[Si](C)(C)CCOC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOC(=O)c1cc(CO)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.8 g of 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl and 1.17 g of anhydrous sodium acetate are stirred overnight at 65° in glacial acetic acid and then boiled under reflux for 3 hours. The reaction mixture is evaporated, the residue is taken up in ethyl acetate and washed with water and sodium hydrogencarbonate, and the organic phase is dried and concentrated. The residue is introduced into 25 ml of ethanol, 6.3 ml of 1N NaOH are added and the mixture is stirred at room temperature for 30 minutes. It is evaporated in vacuo, and the residue is treated with ethyl acetate, washed with water and brine, dried and evaporated. Flash chromatography (N4) yields 4-hydroxymethyl-2-(trimethylsilylethoxycarbonyl)biphenyl as a colourless oil. 1H-NMR (DMSO): 0 ppm (s, 9 H), 0.75 ppm (t, 2 H), 4.1 ppm (t, 2 H), 4.73 ppm (d, 2 H), 5.27 ppm (t, 1H), 7.2-7.7 ppm aromatics.
Reaction SMILES: [C:1]12([CH2:11][C:12](O)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:15]([O:17][C:18]([C:20]1[CH:29]=[C:23]2[C:24]([NH2:28])=[CH:25][CH:26]=[CH:27][N:22]2[N:21]=1)=[O:19])[CH3:16].[Cl-].ClC1N(C)CC[NH+]1C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.C(#N)C.C(N(CC)CC)C>[CH2:15]([O:17][C:18]([C:20]1[CH:29]=[C:23]2[C:24]([NH:28][C:12](=[O:13])[CH2:11][C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:25][CH:26]=[CH:27][N:22]2[N:21]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cc2c(N)cccn2n1
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Agent: CN1CC[NH+](C)C1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1cc2c(NC(=O)CC34CC5CC(CC(C5)C3)C4)cccn2n1
Temperature: 50 °C

Procedure:
A 1.0 M solution of triethylamine in toluene (0.3 mL) is added to a solution of 1-adamantaneacetic acid (14 mg, 80 μmol) and 4-aminopyrazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (12 mg, 60 μmol) in DMF (0.3 mL) under N2. A solution of 2-chloro-1,3-dimethylimidazolinium chloride (20 mg, 120 μmol) in ACN (0.3 mL) is added. The reaction vessel is sealed and the mixture is warmed to 50° C. for 2 h. The mixture is cooled to rt. 50% Sat. aq. NaHCO3 (2 mL) is added. The solution is extracted with Et OAc (2×1 mL). The combined organics are concentrated. Purification by preparative thin layer chromatography (2:1 hexanes:EtOAc) affords the title compound as a light tan solid. 1H NMR (400 MHz, CDCl3) δ: 8.32 (d, 1H), 8.05 (d, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 6.91 (t, 1H), 4.59 (q, 2H), 2.21 (s, 2H), 1.98-2.06 (m, 3H), 1.56-1.78 (m, 12H), 1.46 (t, 3H). LC-MS m/z (M+H+): 382.10.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.Cl>CO>[CH2:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)=[O:10])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(C1CCNCC1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 6 h
Yield: 97.3 %

Procedure:
To a stirred solution of tert-butyl 4-[(dibenzylamino)carbonyl]piperidine-1-carboxylate (EXAMPLE 4, Step 1, 4.0 g, 10.0 mmol) in methanol (550 mL) was added 4N HCl dioxane solution (80 mL, 320 mmol) at 0° C. The mixture was stirred for 6 h and evaporated. The resulting amorphous was dissolved in aqueous ammonia and the mixture was extracted with dichloromethane. The combined extract was dried over magnesium sulfate, and concentrated to afford 3.0 g (99%) of the title compound as a colorless amorphous powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[Si:19]([CH3:22])([CH3:21])[CH3:20].[B:23](OC)([O:26]C)[O:24]C>C1COCC1>[Cl:13][C:14]1[CH:18]=[C:17]([B:23]([OH:26])[OH:24])[S:16][C:15]=1[Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: COB(OC)OC
Reactant: C[Si](C)(C)c1sccc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1sc(B(O)O)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of diisopropyl amine (1.8 ml, 13 mmol) at 0° C. in 50 mL anhdrous THF under nitrogen was added butyllithium, 2.5 M in hexanes (4.6 ml, 12 mmol). The solution was allowed to stir 5 min and then was cooled to −78° C. (3-Chlorothiophen-2-yl)trimethylsilane (2.0 g, 10 mmol) in 5 mL THF at RT was added slowly via cannula, dropwise, over about 10 min. The resulting solution was allowed to stir for 30 min, at which point trimethyl borate (2.4 ml, 21 mmol) was added dropwise. The solution was allowed to stir for 1 h, and was then warmed to 0° C. and quenched by the addition of 25 mL of 2NHCl, and warmed to ambient temperature with stirring. The mixture was extracted three times with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a semisolid. Purification by silica gel chromatography, (0-40% EtOAc/hexanes) provided 4-chloro-5-(trimethylsilyl)thiophen-2-ylboronic acid as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=O)[N:12]=2)=[CH:4][CH:3]=1.Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH3:21]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Reactant: BrCc1ccncc1
Agent: Br
Product: Cc1oc(-c2ccc(OCc3ccncc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially similar to Example 57 from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Example 56) and 4-(bromomethyl)pyridine hydrobromide. MS (m/e): 378.3 (M+1)
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31](S(C)(=O)=O)[N:30]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2].[CH:49]([NH2:52])([CH3:51])[CH3:50]>CN1C(=O)CCC1.O>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31]([NH:52][CH:49]([CH3:51])[CH3:50])[N:30]=2)=[N:8][N:9]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: CC(C)N
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(NC(C)C)n2)cc1
Temperature: 120 °C
Yield: 86.1 %

Procedure:
A glass microwave reaction vessel was charged with N-isopropyl-5-(3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (120 mg, 0.174 mmol) and isopropylamine (0.075 mL, 0.871 mmol) in NMP (1.0 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 1 h. The mixture was diluted with water and filtered. The remaining solid was dried to give the crude product (100 mg), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 668.0 (M+1).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5](Cl)[N:4]=1.[Na+].[Cl-].[CH2:13]([OH:17])[CH:14]([CH3:16])[CH3:15]>>[CH3:15][CH:14]([CH3:16])[CH2:13][O:17][C:5]1[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([NH2:9])[CH:6]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CC(C)CO
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: CC(C)COc1cc(N)nc(N)n1
Reaction time: 10 h
Yield: 75 %

Procedure:
To a solution of 6.9 g (0.30 mol) sodium in 185 ml isobutyl alcohol were added 43.4 g (0.30 mol) 2,4-diamino-6-chloropyrimidine. The mixture was heated under reflux with stirring for 10 h. The reaction mixture was then stirred at 80° C. for a further 36 h. After the reaction was ended the precipitated NaCl was separated off and the solution was concentrated to dryness. The residue was repeatedly taken up in ethanol and again concentrated in order to remove residual isobutyl alcohol. After drying, 6-(2-methylpropoxy)-2,4-diaminopyrimidine (41.3 g, 75%) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:3]1.C1COCC1.[H][H]>C(O)C.[Pd]>[OH:1][C@@H:2]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH2:3]1
Reactant: [H][H]
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)C=Cc3ccncc3)CC[C@@H]12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CCc3ccncc3)CC[C@@H]12
Reaction time: 5 h
Yield: 37.9 %

Procedure:
A solution of 3α-hydroxy-21-(4-pyridylmethylene)-5β-pregnan-20-one (100 mg, 0.245 mmol) in 4 mL each of ethanol and THF containing 20 mg of 5% Pd/C was subjected to hydrogen atmosphere via a balloon, and stirred for 5hours. The catalyst was then filtered off and the solution concentrated in vacuo. The residue was subjected to flash column chromatography eluting with hexane:acetone to give the title compound (38 mg) as a solid; TLC Rf (hexane:acetone 2:1)=0.28.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CN(C)CC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and Dimethylamine were converted to yield Dimethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine as light brown oil, MS: 361 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1=[N:6][N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:8](=[O:15])/[C:9]/1=[C:10](/OCC)\[CH3:11].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH2:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1=[N:6][N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:8](=[O:15])/[C:9]/1=[C:10](/[NH:31][CH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1)\[CH3:11]
Reactant: NCc1ccccn1
Reactant: CCO/C(C)=C1/C(=O)N(c2ccccc2Cl)N=C1CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(\C)NCc1ccccn1
Yield: 95 %

Procedure:
The mixture of the above obtained methyl[(4E)-1-(2-chlorophenyl)-4-(1-ethoxyethylidene)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VII), 1.26 g) and 1-pyridin-2-ylmethanamine (0.262 mL) was stirred at room temperature in toluene (25 mL) for 0.5 h. The solvent was removed in vacuo. The resulting residue was dissolved in a minimum of CH2Cl2 and added dropwise to a stirred solution of 200 mL of cyclohexane resulting in the formation of a brown precipitate that was filtered off. This precipitate was proved to be the pure methyl[(4E)-1-(2-chlorophenyl)-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]ethylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (1.42 g). Yield 95%. MS (ESI+): 399.9; MS (ESI−): 397.8.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:13][N:9]([CH2:10][CH2:11][CH2:12]1)[CH2:8][CH2:7][CH2:6]2)=O.[NH3:14]>CO.C[O-].[Na+].CO>[N:9]12[CH2:13][C:5]([C:3]([NH2:14])=[O:2])([CH2:12][CH2:11][CH2:10]1)[CH2:6][CH2:7][CH2:8]2
Reactant: N
Reactant: COC(=O)C12CCCN(CCC1)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)C12CCCN(CCC1)C2
Temperature: 150 °C
Yield: 38 %

Procedure:
A solution of 1-azabicyclo[3.3.1]nonane-5-carboxylic acid methyl ester (1.83 g, 10 mmol) in ammonia (50 mL) and methanol (20 mL) was sealed in a bomb and heated at 120°-130° C. for 36 hours (gas chromatography indicated that the reaction was incomplete). Three drops of 25% sodium methoxide/methanol were added, and the mixture was heated at 130° C. for 21 hours and at 150° C. for 72 hours, at which time the reaction was essentially complete. The solution was concentrated in vacuo and the residue was partitioned between 1.25N sodium carbonate (50 mL) and methylene chloride (75 mL). The organic layer was separated and the aqueous solution was extracted with methylene chloride (2×40 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo, and recrystallized from acetonitrile to afford 0.64 g (38%) of pale brown solid; mp 172.5°-175.0° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[NH:29][C:30](=[O:35])[C:31]([OH:34])([CH3:33])[CH3:32])[NH:25][C:24](=[O:36])[CH2:23]2>>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:23]3[C:22]4[C:26](=[CH:27][C:28]([NH:29][C:30](=[O:35])[C:31]([OH:34])([CH3:32])[CH3:33])=[C:20]([F:19])[CH:21]=4)[NH:25][C:24]3=[O:36])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)C(C)(C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 41.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 112 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide as starting materials to give N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide (40 mg, 41.8%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.BrC1C=CC=C2C=1NC=C2.C([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:27]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Brc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(N2CCNCC2)c2[nH]ccc2c1
Temperature: 25 °C
Yield: 54 %

Procedure:
The Boc protected indole (200 mg, 1.5 mmol) prepared from 7-bromoindole and N-Boc piperazine as described in Step 1 of Preparation 54A is dissolved in DCM (1 mL). TFA (1 mL) is added and the mixture is stirred at r.t. for about an hour. The mixture is then concentrated to oil, which is taken up in methanol and freebased via SCX purification to afford about 164 mg (54%) of the final compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:38])(=[N:27][C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:26])=[CH:21][CH:20]=1>>[CH2:30]([NH:29][C:28]([N:27]=[S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:20][CH:21]=1)([CH3:38])=[O:26])=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS(=O)(=NC(=O)NCc1ccccc1)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)NCc3ccccc3)cc2)ncc1-c1cccs1
Yield: 26 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (175 mg, 0.65 mmol) with (RS)—S-(4-aminophenyl)-N-(benzylcarbamoyl)-S-methylsulphoximide (179 mg, 0.59 mmol) according to procedure 5c, the desired product is obtained in 26% yield (82 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:14][OH:15]>C(O)C>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@H:13]([NH:12][CH2:11][C@H:9]([OH:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][OH:15])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1
Yield: 75 %

Procedure:
A mixture of (2S)-2-(phenoxymethyl)oxirane (2.30 g), (2S)-2-amino-3-(4-nitrophenyl)-1-propanol (3.0 g) and ethanol (30 ml) was heated under reflux for 18 hours. The reaction mixture was evaporated in vacuo. The residue was triturated with ethyl acetate to give (2S)-3-(4-nitrophenyl)-2-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-1-propanol (3.97 g) as a pale yellow powder. This powder was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:14][C:15]([O:18][C:19](=[O:26])[NH:20][CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:13][C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:24][CH2:25][CH:21]([NH:20][C:19]([O:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:26])[CH2:22]2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cc(Br)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1Cl
Yield: 35.7 %

Procedure:
Prepared as described in Example 5a) using 5-bromo-2-chloro-benzoic acid, ethyl ester (0.50 g), 3-pyrrolidinyl-carbamic acid 1,1-dimethylethyl ester (0.42 g), cesium carbonate (0.86 g), palladium (II) acetate (21 mg) and (R)-BINAP (88 mg) and toluene (3 ml) to afford the subtitle compound as an oil (0.25 g).
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.O.NN>C(O)C>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Yield: 71.7 %

Procedure:
4-Amino-5-chloro-N-(1-(4-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)butyl)piperidin-4-ylmethyl)-2-methoxybenzamide (8.3 g) was dissolved in ethanol (100 ml) and hydrazine hydrate (1.1 ml) was added at room temperature with stirring. The mixture was refluxed with stirring for 3 hr. The precipitated crystals were filtered off and the filtrate was concentrated under reduced pressure to give 4.4 g of 4-amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:10]([NH2:12])=[N:11][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:22]([CH:18]4[O:17][CH2:21][CH2:20][CH2:19]4)=[O:23])[CH2:25][CH2:26]3)=[N:3][C:4]2=[CH:5][C:6]=1[O:15][CH3:16]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC

Procedure:
The process comprises adding 2-chloro-4-amino-6,7-dimethoxyquinazoline together with 1-(2-tetrahydrofuroyl)piperazine to a polar organic reaction solution comprising a polar organic solvent and water. The water is present in a minimum amount effective to obtain the desired product, Terazosin.HCl dihydrate. As can be seen from the exemplary embodiments, the minimum, effective amount of water can vary, depending on the polar organic solvent selected. In the Examples below, the percent volume of water which satisfactorily yielded the desired product ranged roughly from as little as 5% by volume to as much as 20% by volume and more. Other polar organic solvents may require a larger or smaller portion of water than the range demonstrated by the examples, but the determination thereof is well within the purview of one of ordinary skill in the art. The reaction mixture is then heated. Preferably, to ensure highest yields, the reaction mixture is maintained at reflux temperature for as much as 35-55 hours or until one or the other of the reactants is substantially consumed. The reaction mixture is thereafter allowed to cool, preferably to room temperature, and the crystalline Terazosin.HCl dihydrate is collected by filtration.