Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:10][C:11]([CH3:18])([C:15](Cl)=[O:16])[C:12](Cl)=[O:13].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[C:6]2[C:7]=1[C:15](=[O:16])[C:11]([CH3:18])([CH3:10])[C:12]2=[O:13]
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: Cc1ccc(Cl)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(Cl)c2c(c1C)C(=O)C(C)(C)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a mixture of 35.5 ml of 4-chloro-o-xylene and 29.84 g of dimethylmalonyl chloride in 150 ml of dry dichloromethane was added slowly 34.7 g of AlCl3 under the current of nitrogen gas at -10° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 g of ice, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 34.99 g of the title compound as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][C:23](=[O:27])[CH2:24][NH:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:25]([CH3:26])[CH2:24][C:23]([O:22][CH3:21])=[O:27])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNCC(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
N-(tert-Butoxycarbonyl)-phenylalanine (4.85 g, 15 mmol) was condensed with N-methylglycine methyl ester hydrochloride in DMF in the presence of triethylamine, HOBt and WSC.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10](C2C=CC=CC=2)[CH:11]=[C:12](C(F)(F)F)[CH:13]=1)[C:5]([OH:7])=[O:6].[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)#[CH:26]>>[CH3:24][CH:2]([CH3:1])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:11]=[C:12]([C:26]#[C:25][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)[CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)CC(C(=O)O)c1cc(-c2ccccc2)cc(C(F)(F)F)c1
Product: CC(C)CC(C(=O)O)c1cc(C#Cc2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Sonogashira coupling of 4-methyl-2-(5-trifluoromethyl-biphenyl-3-yl)pentanoic acid (intermediate compound 1g) with 1-ethynyl-4-trifluoromethyl-benzene under the conditions described in Example 10; 1H NMR (400 MHz, MeOD) δ ppm 0.86 (dd, J=6.60, 1.96 Hz, 6 H), 1.44 (dt, J=13.45, 6.72 Hz, 1 H), 1.62 (ddd, J=13.82, 7.09, 6.97 Hz, 1 H), 1.87-1.97 (m, 1 H), 3.70 (t, J=7.83 Hz, 1 H), 7.49 (d, J=1.47 Hz, 1 H), 7.57-7.73 (m, 9 H).
Reaction SMILES: CC1(C)C2C=CC(C#CC3C=CC(C(O)=O)=CC=3)=CC=2C(C(C)(C)C)=CC1.[CH2:28]([C:32]1[C:33]2[CH:34]=[C:35]([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([O:52]CC)=[O:51])=[CH:48][CH:47]=3)[CH:36]=[CH:37][C:38]=2[C:39]([CH3:43])([CH3:42])[CH2:40][CH:41]=1)[CH2:29][CH2:30][CH3:31].C(C1C2C=C(C#CC3C=CC(C([O-])=O)=CC=3)C=CC=2C(C)(C)CC=1)CCC>>[CH2:28]([C:32]1[C:33]2[CH:34]=[C:35]([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([OH:52])=[O:51])=[CH:48][CH:47]=3)[CH:36]=[CH:37][C:38]=2[C:39]([CH3:42])([CH3:43])[CH2:40][CH:41]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Agent: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Agent: CCCCC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Product: CCCCC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl )ethynyl]benzoic acid (Compound 80), 22.6 mg (0.06 mmol) of ethyl 4-[(5-butyl-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 74) was converted into the title compound using 6.1 mg (0.146 mmol) of LiOH in H2O.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.ClC1[C:17]([CH2:18][OH:19])=[C:16](Cl)[CH:15]=[CH:14]N=1.ClC1C=NC=C(Cl)C=1CO.BrC1C=NC=C(Cl)C=1COC1CCCCO1>>[Cl:1][C:2]1[C:7]([CH2:8][O:9][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:19]2)=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1c(Cl)ccnc1Cl
Reactant: O=Cc1c(Cl)ccnc1Cl
Agent: Clc1cncc(Br)c1COC1CCCCO1
Agent: OCc1c(Cl)cncc1Cl
Product: Clc1ccnc(Cl)c1COC1CCCCO1

Procedure:
2,4-Dichloro-pyridine-3-carbaldehyde (1.565 g. 8.89 mmol) was reduced to (2,4-dichloro-pyridin-3-yl)-methanol according to the procedure described for the preparation of (3,5-dichloro-pyridin-4-yl)-methanol and subsequently protected with the THP-group according to the procedure described for the preparation 3-bromo-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine to provide the title compound.
Reaction SMILES: N[CH:2]1[CH:7]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH3:20])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH:29](Br)[C:30]1[C:31]([CH3:36])=[CH:32][CH:33]=[CH:34][CH:35]=1.[ClH:38].C(#[N:41])C>C(O)C>[ClH:38].[ClH:38].[F:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([CH:7]3[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH2:20][N:41]4[CH2:36][C:31]5[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:29]4)[CH2:3][CH2:2]3)=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: CC#N
Reactant: Cc1ccccc1C(Br)Br
Reactant: CC(O)CN1CCC(c2noc3cc(F)ccc23)C(N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1Cc2ccccc2C1

Procedure:
To a stirred mixture of 1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.24 g, 7.6 mmol), K2CO3 (1.61 g, 11.7 mmol) in acetonitrile (100 ml) was added α,α-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture was heated at reflux for 4 hours then cooled. The insolubles were filtered. The dark red solution was concentrated down. The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g; eluted with 1% CH3OH in dichloromethane). The product so obtained weighed 940 mg as an oil. This oil was dissolved in ethanol and was treated with a solution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solids were collected and recrystallized again in ethanol to yield off-white crystals (1.01 g), m.p. 240°-243° C.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C([BH:17]C(C(C)C)C=C(C)C)C=C(C)C)(C)C.C=O.[OH:28][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>O>[CH3:30][C:29]1([CH3:31])[C:32]([CH3:34])([CH3:33])[O:35][B:17](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:28]1
Reactant: CC(C)=CC(BC(C=C(C)C)C(C)C)C(C)C
Reactant: CC(C)(O)C(C)(C)O
Reactant: C#CCCCCCC
Agent: C=O
Solvent: O
Product: CCCCCC/C=C/B1OC(C)(C)C(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
1-Octyne (2.95 ml, 20 mmol) was added slowly (˜20 min) to a suspension of freshly prepared di(1-isopropyl-3-methylbut-2-enyl)borane, with the reaction temperature being below 5° C. The mixture formed was stirred at 0° C. for 1 hour, slowly quenched with H2O (3 ml) (with some gas evolution occurring) and stirred at RT for 0.5 hour, after which a solution of formaldehyde (1.50 ml, 20 mmol, 37% strength by weight solution in water) was added all at once (exothermic reaction, cooling bath necessary). The reaction mixture was stirred at RT for 1 hour and then admixed with pinacol (2.60 g, 22 mmol). After stirring at RT for 24 hours, the mixture was diluted with H2O (40 ml) and extracted with heptane (40 ml), after which the organic extract was washed with H2O (5×25 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue obtained was carefully distilled under reduced pressure (bulb tube), giving 3.19 g of the product (13.39 mmol, 67% yield) in the form of a colorless liquid, b.p. 70-80° C. (0.15 mm of Hg); IR (film) 2928, 1639, 1363, 1319, 1146 cm−1; 1H-NMR (300 MHz, acetone-d6) 6.55 (dt, 1H, J=18.0, 6.6 Hz), 5.35 (dt, 1H, J=18.0, 1.5 Hz), 2.17-2.09 (m, 2H), 1.50-1.20 (m, 8H), 1.21 (s, 12H), 0.90-0.85 (m, 3H); 13C-NMR (75.4 MHz, acetone-d6) 155.0, 83.6, 36.5, 32.5, 29.7, 29.2, 25.2, 23.3, 14.4;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][NH2:27])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][NH:27][C:37](=[O:39])[CH3:38])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CN)c1nnc(C)n1-2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Temperature: 0 °C

Procedure:
To a solution of ((1S,2S)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-yl)methanamine (Compound 206; 50 mg, 0.126 mmol) in DCM (2 mL) was added N,N-diisopropylethylamine (43.9 μl, 0.251 mmol). Once the reaction was cooled to 0° C., a solution of acetic anhydride in DCM (140 mg/mL) (14.23 μl, 0.151 mmol) was added. The reaction was stirred at 0° C. for 15 min before an aqueous solution of NaHCO3(sat.) was added for the quench. The product was extracted with DCM (repeated 4 times). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography (DCM/MeOH 10:0 to 9:1) to give the desired product as an off-white solid (33 mg). LRMS (M+H)+: 440 m/z. 1H NMR (two conformers detected in ˜1:1 ratio) (400 MHz, DMSO-d6) δ 8.08 (t, J=5.15 Hz, 0.5H), 7.75 (t, J=4.92 Hz, 0.5H), 7.44-7.56 (m, 4H), 3.45-3.51 (m, 1H), 2.78-2.86 (m, 0.5H), 2.64-2.72 (m, 0.5H), 2.56-2.63 (m, 3H), 2.35-2.42 (m, 3H), 2.13-2.22 (m, 0.5H), 2.00 (dd, J=5.04, 8.93 Hz, 0.5H), 1.86 (s, 1.5H), 1.71 (s, 1.5), 1.58 (m, 1.5H), 1.57 (m, 1.5H), 1.22-1.37 (m, 1H), 0.99 (dd, J=5.26, 9.16 Hz, 0.5H), 0.58 (t, J=5.95 Hz, 0.5H).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OC(C)C)(C)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:28]([C:25]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:12]([CH3:13])[CH2:11][N:6]3[CH2:7][CH2:8][CH2:9][CH2:10]3)[C:27]=2[CH:26]=1)=[O:30]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCc3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
Thionyl chloride (3.6 cc) is added to a suspension, cooled to 5° C., of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (2.7 g) in methylene chloride (70 cc). The suspension is stirred for 3 hours at 25° C. and then concentrated to dryness at 30° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow residue which is taken up with methylene chloride (50 cc) at 5° C. 3-Chlorobenzylamine (6.9 g) is added and the mixture is stirred for 12 hours at 25° C., and saturated sodium bicarbonate solution (150 cc) is then added. The mixture is extracted with ethyl acetate (2×100 cc). The organic phase is washed successively with distilled water (100 cc) and with brine (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give a brown oil which is purified by chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica (0.06-0.2 mm), eluting with methylene chloride (1 liter) and collecting 40-cc fractions. Fractions 12 to 24 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a cream-coloured solid which is taken up in isopropyl ether (20 cc). The solid is separated by filtration, washed with isopropyl ether (2×5 cc) and dried at 40° C. under reduced pressure (1 mm Hg; 0.13 kPa). N-(3-Chlorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (2 g) is obtained in the form of a yellow solid, m.p. approximately 80° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:20])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([NH2:21])[CH:3]=1.Br[CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br.CCN(C(C)C)C(C)C>C(O)CO.O>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:20])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([N:21]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1c(Cl)cccc1Cn1c(C)nc2c(Br)cc(N)cc21
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(C)nc2c(Br)cc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
A mixture of 7-bromo-3-(3-chloro-2-methylbenzyl)-2-methyl-3H-benzo[d]imidazol-5-amine (85 g, 233 mmol), 1-bromo-2-(2-bromoethoxy)ethane (108 g, 466 mmol) and DIPEA (60 g, 466 mmol) in ethylene glycol (1 L) was stirred at 100° C. for 18 h. It was cooled to rt, and diluted with water (1 L) and extracted with DCM (500 mL×4). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated. The residue was purified by column chromatography (eluted with petroleum ether/ethyl acetate=1/1) to give the product (48 g, 47.5%) as a yellow solid; LC/MS: MS (ES+) m/e 434 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 2.46 (s, 3H), 3.04-3.07 (m, 4H), 3.68-3.72 (m, 4H), 5.47 (s, 2H), 6.04 (d, J=8.1 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 7.06 (t, J=8.1 Hz, 1H), 7.09 (d, J=2.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)NCc3ccccn3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)NCc3ccccn3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-(2-picolylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (180 mg), 1 N aqueous sodium hydroxide solution (0.77 ml), ethanol (1 ml), and tetrahydrofuran (1 ml) was stirred at room temperature for one hour. 1 N hydrochloric acid (0.77 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-(2-picolylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionic acid (120 mg, yield: 71%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 83–85° C. (decomposition).
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:24]=[CH:23][C:6]2[O:7][C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:12]3[CH:17]=[CH:16][N+:15]([CH3:18])=[CH:14][CH:13]=3)=[N:11][C:5]=2[CH:4]=1.[BH4-].[Na+]>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:24]=[CH:23][C:6]2[O:7][C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: C[n+]1ccc(C2=Nc3cc(Cl)ccc3Oc3ccccc32)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CN1CC=C(C2=Nc3cc(Cl)ccc3Oc3ccccc32)CC1
Product: Cl

Procedure:
A 6.23 g. portion of the above iodide salt is suspended in 150 ml. of ethanol and the mixture is cooled in an ice salt bath. A 0.64 g. portion of sodium borohydride is added in portions over 1 minute and the resulting solution is stirred with ice bath cooling for an additional 30 minutes. The reaction is quenched with one ml. of acetone and diluted with 500 ml. of ether. The ether solution is washed with three 250 ml. portions of water, dried with brine and made acidic with hydrochloric acid. The mixture is cooled and filtered giving a tan solid which is crystallized from acetone-ethanol-dimethylformamide yielding the desired product as the hydrochloride, mp. 213°-215° C. Failure to acidify the above ether solution produces compound as a base mp. 143°-145° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][S:20]([C:23]3[S:24][C:25](Br)=[CH:26][CH:27]=3)(=[O:22])=[O:21])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.[C:39]([O-])([O-])=[O:40].[K+].[K+].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.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][S:20]([C:23]3[S:24][C:25]([C:33]4[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=4)=[CH:26][CH:27]=3)(=[O:22])=[O:21])[C:17]([O:40][CH3:39])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(NS(=O)(=O)c3ccc(Br)s3)cc2CC1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2c(cc1NS(=O)(=O)c1ccc(-c3ccc(Cl)cc3)s1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 60 °C
Yield: 86 %

Procedure:
A solution of the bromo intermediate D5 (1.20 g, 0.0023 moles), 4-chlorophenylboronic acid (0.55 g, 0.0034 moles), K2CO3 (2M solution, 15 ml), ethanol (15 ml) and toluene (50 ml) at room temperature was degassed by bubbling argon through the solution for 10 minutes. Pd(PPh3)4 (0.4 g, 0.000375 moles) was added and the mixture heated at 60° C. under argon for 4 hours. Upon cooling the mixture was partitioned between water and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (×3) and the combined organic phase washed with water, brine then dried over anhydrous MgSO4. The solution was evaporated to dryness then purified by chromatography over silica eluting, with hexane up to 50% EtOAc/hexane, affording the title compound D7 as a white foam (1.09 g, 86%). M-H 547. 1H NMR: δ CDCl3 1.47 (9H, s) 2.83(4H, m), 3.50 (4H, m), 3.66 (3H,s), 6.55 (1H, s), 6.96 (1H, s), 7.12 (1H, d), 7.33–7.50 (5H, m).
Reaction SMILES: [CH:1]([NH2:14])([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.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23]N)=[CH:18][N:17]=1.CCN(CC)CC>>[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23][NH:14][CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][N:17]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: NCc1cnc(N)nc1N
Solvent: CCN(CC)CC
Product: Nc1ncc(CNC(c2ccccc2)c2ccccc2)c(N)n1

Procedure:
W=CH2NH; X=CH; Z=non-linked hydrogens on each phenyl group; m=n=0) is prepared similarly to N-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)amino]benzhydrylamine as disclosed above by using benzhydrylamine (366 mg, 2.0 mmol), 2,4-diamino-5-aminomethylpyrimidine (278 mg, 2.0 mmol), mg, 2 mmol), and BH3.Et3N (75 mg, 6.6 mmol). The product can be purified by chromatography.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[H-].[Na+].[CH2:20](Br)[C:21]#[CH:22].CO>CN(C)C=O>[C:4]1(=[O:12])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:22][C:21]#[CH:20])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12
Reactant: C#CCBr
Reactant: O=C1c2ccccc2C(=O)N1CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C#CCOCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a stirred solution of compound 15 (1.39 g, 5.91 mmol) in N,N-dimethylformamide (25 mL) was added NaH (0.33 g, 80%) dropwise. After complete NaH addition, stirring was continued for 0.5 h at room temperature and then cooled to 0° C. Propargyl bromide 4 (1.24 μL, 11.13 mmol) was added, and stirring was continued for 0.5 h at 0° C., then for 2 h at room temperature. After careful addition of methanol to decompose excess NaH, the solvent was evaporated and crude product was purified by flash column chromatography (3:2 to 1:1 to 2:3 hexane-ethyl acetate) to give compound 16 as a solid (591 mg, 36.6%) having an RF of 0.41 (solvent 3:2 hexane-ethyl acetate). See FIG. 9.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:25](=O)[NH2:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:25]#[N:26])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(N)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCCC1C#N
Temperature: -5 °C
Yield: 97.4 %

Procedure:
Acetonitrile (220 mL) and DMF (3.82 mL, 49.4 mmol) were added to a 500 mL round bottom flask equipped with stir bar. Cooled the mixture down to −5° C. and to it added oxalyl chloride (24.7 mL, 49.4 mmol, 2 M dichloromethane). The resulting mixture was stirred for 15 min. This was followed by addition of solution of 2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (9.4 g, 41.2 mmol) in acetonitrile (50 mL) and pyridine (8.3 mL, 103 mmol). Reaction mixture was left stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL). The organic phase was successively washed with water (300 mL) and brine (200 mL), dried (sodium sulfate), filtered and concentrated in vacuo to isolate the title compound (8.44 g, 97%) as a yellow solid. 1H-NMR (CDCl3), δ(ppm): 5.23 (bs, 1H), 4.03 (bs, 1H), 2.93 (t, 1H), 1.75 (m, 5H), 1.46 (m, 10H).
Reaction SMILES: CO[CH:3]([C:19](O)=[O:20])[CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].O1CCCC1.[BH4-].[Li+]>C(COC)OC>[OH:20][CH2:19][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18]
Reactant: COC(CC[C@@]12CCCc3cccc(c31)NC2=O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C1Nc2cccc3c2[C@@]1(CCCCO)CCC3
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
(S)-2a-(3-methoxycarboxypropyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (4.1 g, 15 mmol) was dissolved in dimethoxyethane (60 ml). Then, tetrahydrofuran solution of 1.6 M lithiumborohydride (9.0 ml, 18 mmol) was added to the resulting solution and stirred at room temperature for two days. The solvent was evaporated from the reaction mixture, and ethyl acetate, water and hydrochloric acid (1N) were added to the resulting residue. The reaction product was extracted with ethyl acetate, and the extracted product was washed with saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent. The resulting product was separated and purified by means of silica gel column chromatography, whereby 2.15 g (yield 58%) of the above-described object compound could be obtained.